Treatment of liver diseases with cell death inducing DFFA like effector B (CIDEB) inhibitors

ABSTRACT

The present disclosure provides methods of treating subjects having a liver disease, and methods of identifying subjects having an increased risk of developing liver disease.

REFERENCE TO A SEQUENCE LISTING

This application includes a Sequence Listing submitted electronically as a text file named 18923806201SEQ, created on Dec. 21, 2021, with a size of 2,576 kilobytes. The Sequence Listing is incorporated herein by reference.

FIELD

The present disclosure relates generally to the treatment of subjects having a liver disease with cell death inducing DFFA like effector B (CIDEB) inhibitors, patatin-like phospholipase domain containing 3 (PNPLA3) inhibitors, or hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitors, or any combination thereof, and methods of identifying subjects having an increased risk of developing a liver disease.

BACKGROUND

Chronic liver disease and liver cirrhosis are leading causes of morbidity and mortality in the United States, accounting for 38,170 deaths (1.5% of total deaths) in 2014 (Kochanek et al., Nat'l. Vital Stat. Rep., 2016, 65, 1-122). The most common etiologies of liver cirrhosis in the U.S. are alcoholic liver disease, chronic hepatitis C, and nonalcoholic fatty liver disease (NAFLD), together accounting for about 80% of patients awaiting liver transplant between 2004 and 2013 (Wong et al., Gastroenterology, 2015, 148, 547-555). The estimated prevalence of NAFLD in the U.S. is between 19 and 46 percent (Browning et al., Hepatology, 2004, 40, 1387-1395; Lazo et al., Am. J. Epidemiol., 2013, 178, 38-45; and Williams et al., Gastroenterology, 2011, 140, 124-131) and has been rising over time (Younossi et al., Clin. Gastroenterol. Hepatol., 2011, 9, 524-530), likely in conjunction with increased prevalence of obesity, which is one of its primary risk factors (Cohen et al., Science, 2011, 332, 1519-1523). While significant advances have been made in the treatment of hepatitis C, there are currently no evidence-based treatments for alcoholic or nonalcoholic liver disease or liver cirrhosis. Identifying naturally occurring genetic variants that protect from liver damage and liver disease outcomes can be a pathway to identify novel therapeutic targets for liver disease (Abul-Husn et al. N. Engl. J. Med., 2018, 378, 1096-106).

CIDEB is expressed in the liver and small intestine and has been shown to play roles in regulating various aspects of lipid metabolism. CIDEB may participate in lipid metabolism by regulating lipid droplet fusion and very low density lipoprotein (VLDL) lipidation by interacting with ApoB. CIDEB is also required for the biogenesis of VLDL transport vesicles and for chylomicron lipidation in the small intestine. In addition, CIDEB regulates hepatic SREBP activation (master regulators of lipid metabolism) by selectively promoting ER-to-Golgi delivery of the SREBP/SCAP complex. Sterol depletion induces SCAP to interact with CIDEB, which also binds Sec12, the GEF of Sar1, thereby enriching SCAP/SREBP at ER exit sites and increasing the packaging of SREBP/SCAP into COPII-coated vesicles.

SUMMARY

The present disclosure provides methods of treating a subject having a liver disease or at risk of developing a liver disease, the methods comprising administering a CIDEB inhibitor to the subject.

The present disclosure also provides methods of treating a subject with a CIDEB inhibitor, wherein the subject has a liver disease or is at risk of developing a liver disease, the methods comprising the steps of: determining whether the subject has a CIDEB variant nucleic acid molecule by: obtaining or having obtained a biological sample from the subject; and performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising the CIDEB variant nucleic acid molecule; and administering or continuing to administer the CIDEB inhibitor in a standard dosage amount to a CIDEB reference subject; and administering or continuing to administer the CIDEB inhibitor in a dosage amount that is the same as or less than a standard dosage amount to a subject that is heterozygous or homozygous for the CIDEB variant nucleic acid molecule; wherein the presence of a genotype having the CIDEB variant nucleic acid molecule indicates the subject has a decreased risk of developing the liver disease or has a decreased risk of developing a more severe form of the liver disease.

The present disclosure also provides methods of identifying a subject having an increased risk of developing a liver disease, the methods comprising: determining or having determined the presence or absence of a CIDEB variant nucleic acid molecule in a biological sample obtained from the subject; wherein: when the subject is CIDEB reference, the subject has an increased risk of developing the liver disease; and when the subject is heterozygous or homozygous for the CIDEB variant nucleic acid molecule, the subject has a decreased risk of developing the liver disease or has a decreased risk of developing a more severe form of the liver disease.

The present disclosure also provides therapeutic compositions that treat or inhibit a liver disease for use in the treatment of a liver disease in a subject having a CIDEB variant nucleic acid molecule comprising: 14:24305635:A:AGTAG, 14:24305641:A:C, 14:24305650:G:A, 14:24305657:C:A, 14:24305662:G:T, 14:24305667:T:C, 14:24305671:C:A, 14:24305671:C:G, 14:24305701:A:T, 14:24305709:C:T, 14:24305718:A:G, 14:24305721:T:C, 14:24305728:G:GGCCTT, 14:24305743:T:C, 14:24305948:T:C, 14:24305966:C:T, 14:24305974:T:C, 14:24305980:TCA:T, 14:24305988:C:T, 14:24306014:C:T, 14:24306034:A:C, 14:24306041:C:G, 14:24306044:G:A, 14:24306047:G:A, 14:24306051:T:G, 14:24306064:T:C, 14:24306074:A:G, 14:24306077:G:C, 14:24306082:A:G, 14:24306083:T:A, 14:24306095:G:A, 14:24306122:A:G, 14:24306134:C:G, 14:24306373:C:G, 14:24306379:T:C, 14:24306382:G:A, 14:24306383:G:T, 14:24306426:T:G, 14:24306437:C:G, 14:24306439:G:C, 14:24306442:A:G, 14:24306444:A:G, 14:24306457:C:T, 14:24306463:C:T, 14:24306469:C:T, 14:24306480:A:G, 14:24306486:A:C, 14:24306504:A:G, 14:24306519:A:G, 14:24307382:G:C, 14:24307405:A:G, 14:24307417:A:T, 14:24307421:T:A, 14:24307441:C:A, 14:24307444:A:C, 14:24307444:A:G, 14:24307450:C:CGCTG, 14:24307461:TG:T, 14:24307469:AG:A, 14:24307474:C:T, 14:24307475:A:G, 14:24307833:G:C, 14:24307851:T:TAC, 14:24306426:T:C, 14:24307849:G:C, 14:24307448:G:T, 14:24305671:C:T, 14:24305663:C:T, 14:24305686:C:G, 14:24307829:A:C, 14:24307818:CTGAG:C, 14:24307856:C:T, 14:24306423:T:C, 14:24306061:AC:A, 14:24307390:C:T, 14:24306382:G:T, 14:24306373:C:T, 14:24305733:T:C, 14:24307858:T:C, 14:24306387:C:T, 14:24305637:T:C, 14:24306062:C:T, 14:24307853:C:G, 14:24307450:C:G, 14:24306052:TG:T, 14:24305673:G:A, 14:24306043:C:T, 14:24307834:G:A, 14:24306417:C:T, 14:24307451:G:A, 14:24307436:A:C, 14:24305953:ACTTT:A, 14:24306489:G:T, 14:24307441:C:T, 14:24306375:C:T, 14:24305657:C:G, 14:24306427:C:T, 14:24306524:C:T, 14:24307516:C:A, 14:24307840:G:C, 14:24307501:A:G, 14:24305968:A:C, 14:24305986:C:T, 14:24307441:C:G, 14:24307459:G:T, 14:24306017:T:A, 14:24307424:G:A, 14:24306072:G:T, 14:24307423:C:T, 14:24307450:C:T, 14:24306420:G:A, 14:24307454:G:A, 14:24305653:C:T, 14:24307442:G:A, 14:24306002:C:T, 14:24306076:C:T, 14:24305664:C:T, 14:24305961:TG:T, 14:24305706:A:G, 14:24305946:C:T, 14:24306455:G:C, 14:24307468:G:A, 14:24307825:A:C, 14:24306110:G:A, 14:24305710:C:T, 14:24307483:C:T, 14:24306459:A:G, 14:24305754:C:T, 14:24305650:G:C, 14:24305691:C:T, 14:24306508:G:C, 14:24306039:G:T, 14:24306139:T:C, 14:24306391:T:C, 14:24306373:C:A, 14:24307498:C:T, 14:24307415:G:A, 14:24306138:CTG:C, 14:24307453:T:C, 14:24305692:G:A, 14:24305683:C:G, 14:24307484:G:A, 14:24307385:C:T, 14:24306519:A:T, 14:24307839:A:C, 14:24305965:C:T, 14:24305988:CAT:C, 14:24306087:C:G, 14:24307439:C:T, 14:24307477:A:C, 14:24306436:G:T, 14:24306507:A:G, 14:24307397:C:T, 14:24307495:G:A, 14:24306034:A:T, 14:24306013:G:A, 14:24307381:A:G, 14:24306383:G:C, 14:24305638:A:G, 14:24307420:G:A, 14:24306020:C:T, 14:24306470:A:C, 14:24307435:C:T, 14:24306469:C:G, 14:24306451:C:T, 14:24306403:G:A, 14:24307515:C:G, 14:24307489:A:G, 14:24307414:C:T, 14:24306483:A:G, 14:24305755:G:A, 14:24305766:C:T, 14:24306064:T:G, 14:24307516:C:G, 14:24305766:C:G, 14:24306489:G:A, 14:24306097:T:C, 14:24305763:T:G, 14:24307447:G:A, 14:24307402:G:A, 14:24305972:C:G, 14:24306423:T:G, 14:24305974:T:TG, 14:24307411:T:C, 14:24306121:T:C, 14:24307516:C:T, 14:24306424:C:T, 14:24306039:G:C, 14:24307853:C:A, 14:24306388:A:G, 14:24305990:T:C, 14:24307822:G:GT, 14:24305640:G:A, 14:24307418:T:C, 14:24305758:G:C, 14:24306131:C:T, 14:24305953:A:G, 14:24305730:C:A, 14:24306418:A:G, 14:24306059:AC:A, 14:24307842:G:A, 14:24307837:T:G, 14:24306095:G:T, 14:24306109:C:T, 14:24307822:G:A, 14:24306077:G:A, 14:24307824:A:T, 14:24306080:C:T, 14:24305649:C:T, 14:24306433:G:GA, 14:24306420:G:C, 14:24305658:T:G, 14:24306472:C:T, 14:24307412:TC:T, 14:24306062:C:A, 14:24306044:G:C, 14:24306047:G:T, 14:24306126:CAG:C, 14:24306449:C:G, 14:24307391:G:A, or 14:24307857:A:C, according to GRCh38/hg38 human genome assembly coordinates.

The present disclosure also provides compositions comprising a CIDEB inhibitor, a PNPLA3 inhibitor, or an HSD17B13 inhibitor, or any combination thereof, for use in the treatment of a liver disease in a subject having a CIDEB variant nucleic acid molecule comprising: 14:24305635:A:AGTAG, 14:24305641:A:C, 14:24305650:G:A, 14:24305657:C:A, 14:24305662:G:T, 14:24305667:T:C, 14:24305671:C:A, 14:24305671:C:G, 14:24305701:A:T, 14:24305709:C:T, 14:24305718:A:G, 14:24305721:T:C, 14:24305728:G:GGCCTT, 14:24305743:T:C, 14:24305948:T:C, 14:24305966:C:T, 14:24305974:T:C, 14:24305980:TCA:T, 14:24305988:C:T, 14:24306014:C:T, 14:24306034:A:C, 14:24306041:C:G, 14:24306044:G:A, 14:24306047:G:A, 14:24306051:T:G, 14:24306064:T:C, 14:24306074:A:G, 14:24306077:G:C, 14:24306082:A:G, 14:24306083:T:A, 14:24306095:G:A, 14:24306122:A:G, 14:24306134:C:G, 14:24306373:C:G, 14:24306379:T:C, 14:24306382:G:A, 14:24306383:G:T, 14:24306426:T:G, 14:24306437:C:G, 14:24306439:G:C, 14:24306442:A:G, 14:24306444:A:G, 14:24306457:C:T, 14:24306463:C:T, 14:24306469:C:T, 14:24306480:A:G, 14:24306486:A:C, 14:24306504:A:G, 14:24306519:A:G, 14:24307382:G:C, 14:24307405:A:G, 14:24307417:A:T, 14:24307421:T:A, 14:24307441:C:A, 14:24307444:A:C, 14:24307444:A:G, 14:24307450:C:CGCTG, 14:24307461:TG:T, 14:24307469:AG:A, 14:24307474:C:T, 14:24307475:A:G, 14:24307833:G:C, 14:24307851:T:TAC, 14:24306426:T:C, 14:24307849:G:C, 14:24307448:G:T, 14:24305671:C:T, 14:24305663:C:T, 14:24305686:C:G, 14:24307829:A:C, 14:24307818:CTGAG:C, 14:24307856:C:T, 14:24306423:T:C, 14:24306061:AC:A, 14:24307390:C:T, 14:24306382:G:T, 14:24306373:C:T, 14:24305733:T:C, 14:24307858:T:C, 14:24306387:C:T, 14:24305637:T:C, 14:24306062:C:T, 14:24307853:C:G, 14:24307450:C:G, 14:24306052:TG:T, 14:24305673:G:A, 14:24306043:C:T, 14:24307834:G:A, 14:24306417:C:T, 14:24307451:G:A, 14:24307436:A:C, 14:24305953:ACTTT:A, 14:24306489:G:T, 14:24307441:C:T, 14:24306375:C:T, 14:24305657:C:G, 14:24306427:C:T, 14:24306524:C:T, 14:24307516:C:A, 14:24307840:G:C, 14:24307501:A:G, 14:24305968:A:C, 14:24305986:C:T, 14:24307441:C:G, 14:24307459:G:T, 14:24306017:T:A, 14:24307424:G:A, 14:24306072:G:T, 14:24307423:C:T, 14:24307450:C:T, 14:24306420:G:A, 14:24307454:G:A, 14:24305653:C:T, 14:24307442:G:A, 14:24306002:C:T, 14:24306076:C:T, 14:24305664:C:T, 14:24305961:TG:T, 14:24305706:A:G, 14:24305946:C:T, 14:24306455:G:C, 14:24307468:G:A, 14:24307825:A:C, 14:24306110:G:A, 14:24305710:C:T, 14:24307483:C:T, 14:24306459:A:G, 14:24305754:C:T, 14:24305650:G:C, 14:24305691:C:T, 14:24306508:G:C, 14:24306039:G:T, 14:24306139:T:C, 14:24306391:T:C, 14:24306373:C:A, 14:24307498:C:T, 14:24307415:G:A, 14:24306138:CTG:C, 14:24307453:T:C, 14:24305692:G:A, 14:24305683:C:G, 14:24307484:G:A, 14:24307385:C:T, 14:24306519:A:T, 14:24307839:A:C, 14:24305965:C:T, 14:24305988:CAT:C, 14:24306087:C:G, 14:24307439:C:T, 14:24307477:A:C, 14:24306436:G:T, 14:24306507:A:G, 14:24307397:C:T, 14:24307495:G:A, 14:24306034:A:T, 14:24306013:G:A, 14:24307381:A:G, 14:24306383:G:C, 14:24305638:A:G, 14:24307420:G:A, 14:24306020:C:T, 14:24306470:A:C, 14:24307435:C:T, 14:24306469:C:G, 14:24306451:C:T, 14:24306403:G:A, 14:24307515:C:G, 14:24307489:A:G, 14:24307414:C:T, 14:24306483:A:G, 14:24305755:G:A, 14:24305766:C:T, 14:24306064:T:G, 14:24307516:C:G, 14:24305766:C:G, 14:24306489:G:A, 14:24306097:T:C, 14:24305763:T:G, 14:24307447:G:A, 14:24307402:G:A, 14:24305972:C:G, 14:24306423:T:G, 14:24305974:T:TG, 14:24307411:T:C, 14:24306121:T:C, 14:24307516:C:T, 14:24306424:C:T, 14:24306039:G:C, 14:24307853:C:A, 14:24306388:A:G, 14:24305990:T:C, 14:24307822:G:GT, 14:24305640:G:A, 14:24307418:T:C, 14:24305758:G:C, 14:24306131:C:T, 14:24305953:A:G, 14:24305730:C:A, 14:24306418:A:G, 14:24306059:AC:A, 14:24307842:G:A, 14:24307837:T:G, 14:24306095:G:T, 14:24306109:C:T, 14:24307822:G:A, 14:24306077:G:A, 14:24307824:A:T, 14:24306080:C:T, 14:24305649:C:T, 14:24306433:G:GA, 14:24306420:G:C, 14:24305658:T:G, 14:24306472:C:T, 14:24307412:TC:T, 14:24306062:C:A, 14:24306044:G:C, 14:24306047:G:T, 14:24306126:CAG:C, 14:24306449:C:G, 14:24307391:G:A, or 14:24307857:A:C, according to GRCh38/hg38 human genome assembly coordinates.

The present disclosure also provides methods of treating a subject having a liver disease or at risk of developing a liver disease, wherein the subject is heterozygous or homozygous for a PNPLA3 variant nucleic acid molecule encoding PNPLA3 Ile148Met or Ile144Met polypeptide, the methods comprising administering to the subject: i) a CIDEB inhibitor; ii) a combination of a CIDEB inhibitor and a PNPLA3 inhibitor; iii) a combination of a CIDEB inhibitor and an HSD17B13 inhibitor; or iv) a combination of a CIDEB inhibitor, a PNPLA3 inhibitor, and an HSD17B13 inhibitor.

The present disclosure also provides methods of treating a subject having a liver disease or at risk of developing a liver disease, wherein: when the subject is homozygous for a nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide, the subject is administered: i) a CIDEB inhibitor in an amount that is the same as or greater than a standard dosage amount; ii) a combination of a CIDEB inhibitor in an amount that is the same as or greater than a standard dosage amount and a PNPLA3 inhibitor; iii) a combination of a CIDEB inhibitor in an amount that is the same as or greater than a standard dosage amount and an HSD17B13 inhibitor; or iv) a combination of a CIDEB inhibitor in an amount that is the same as or greater than a standard dosage amount, aPNPLA3 inhibitor, and an HSD17B13 inhibitor; and when the subject is not homozygous for a nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide (i.e., is a carrier for a loss-of-function HSD17B13), the subject is administered: i) a CIDEB inhibitor in an amount that is less than a standard dosage amount; ii) a combination of a CIDEB inhibitor in an amount that is less than a standard dosage amount and a PNPLA3 inhibitor; iii) a combination of a CIDEB inhibitor in an amount that is less than a standard dosage amount and an HSD17B13 inhibitor; or iv) a combination of a CIDEB inhibitor in an amount that is less than a standard dosage amount, aPNPLA3 inhibitor, and an HSD17B13 inhibitor.

The present disclosure also provides methods of treating a subject with a CIDEB inhibitor, wherein the subject has a liver disease or is at risk of developing a liver disease, the methods comprising: determining whether the subject has a PNPLA3 variant nucleic acid molecule encoding a PNPLA3 Ile148Met or Ile144Met polypeptide by: obtaining or having obtained a biological sample from the subject; and performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising the PNPLA3 variant nucleic acid molecule; and administering or continuing to administer the CIDEB inhibitor in an amount that is the same as or greater than a standard dosage amount, or in combination with an HSD17B13 inhibitor and/or a PNPLA3 inhibitor to a subject that is heterozygous or homozygous for the PNPLA3 variant nucleic acid molecule; wherein the presence of a genotype having the PNPLA3 variant nucleic acid molecule encoding a PNPLA3 Ile148Met or Ile144Met polypeptide indicates that the subject is a candidate for treatment with the CIDEB inhibitor.

The present disclosure also provides methods of treating a subject with a CIDEB inhibitor, wherein the subject has a liver disease or is at risk of developing a liver disease, the methods comprising: determining whether the subject has a nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide by: obtaining or having obtained a biological sample from the subject; and performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising the nucleic acid molecule encoding the reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide; and administering or continuing to administer the CIDEB inhibitor, or in combination with an HSD17B13 inhibitor and/or a PNPLA3 inhibitor, to a subject that is heterozygous or homozygous for the nucleic acid molecule encoding the reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide; wherein the presence of a genotype having the nucleic acid molecule encoding the reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide indicates the subject is a candidate for treatment with the CIDEB inhibitor.

The present disclosure also provides methods of treating a subject, wherein the subject is overweight, obese, has increased body mass index (BMI), has a high percentage of liver fat, or has high adiposity, the methods comprising administering to the subject a CIDEB inhibitor, or a CIDEB inhibitor in combination with a PNPLA3 inhibitor and/or an HSD17B13 inhibitor.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects and together with the description serve to explain the principles of the present disclosure.

FIG. 1 shows an association of rare coding variants in CIDEB with liver disease risk. The Figure shows the association with liver disease across etiology and severity spectrum for rare pLOF variants in CIDEB (top), rare coding variants in CIDEB (middle) and the HSD17B13 splice variant (gray, heterozygous variant genotype compared with reference homozygous genotype; open circles, homozygous variant genotype compared with reference homozygous genotype). Abbreviations: OR; odds ratio, CI, confidence interval.

FIG. 2 shows an association of rare coding variants in CIDEB with liver histopathology phenotypes in bariatric surgery patients. Panel a shows the breakdown of liver histopathology categories (i.e., normal liver, simple steatosis, NASH or fibrosis) among carriers and non-carriers of rare coding (i.e., pLOF and missense) variants in CIDEB. Panel b shows the distribution of nonalcoholic fatty liver disease activity score at liver histopathology among carriers and non-carriers of rare coding (i.e., pLOF plus missense) variants in CIDEB. Data are from perioperative liver biopsies of participants in the GHS bariatric surgery cohort. Abbreviations: pLOF, predicted loss of function; NASH, nonalcoholic steatohepatitis; NALD, nonalcoholic fatty liver disease.

FIG. 3 shows associations with metabolic traits of rare coding variants in CIDEB. Associations estimates in blue are for rare coding (pLOF and missense) variants, while association estimates in red are for rare pLOF variants only. Panel a shows associations with continuous traits, while Panel b shows associations with binary outcomes traits. Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein; BMI, Body mass index; WHRadjBMI, Waist-hip ratio adjusted for BMI; DBP, Diastolic blood pressure; SBP, Systolic blood pressure; pLOF, predicted loss of function; CI, Confidence interval; kg/m², kilograms per square meter; mg/DL, milligrams per deciliter; and mmHg, millimeter of mercury.

FIG. 4 shows a visualization of the interaction between the burden of rare coding variants in CIDEB and body mass index on alanine aminotransferase levels. CIDEB rare coding (pLOF and missense) variants (Panel a) and CIDEB rare pLOF variants alone (Panel b) were associated with a larger decrease in ALT when individuals have higher body mass index compared to individuals with a lower body mass index. Interaction p-values were used to determine whether this difference in association with ALT by BMI was statistically significant. Abbreviations: ALT, alanine aminotransferase; BMI, body mass index; pLOF, predicted loss of function; AAF, alternate allele frequency; SD, standard deviation; U/L, units per liter.

FIG. 5 shows a visualization of the interaction between rare coding variants in CIDEB and body mass index. Panel a shows the interaction of CIDEB genotype (i.e., rare pLOF variants) and body mass index on alanine aminotransferase level. Panel b shows the interaction of CIDEB genotype (i.e., rare pLOF and missense variants) and body mass index on alanine aminotransferase level. Abbreviations: pLOF, predicted loss of function; SD, standard deviation; P, p-value; ALT, alanine aminotransferase; BMI, body mass index; U/L, units per liter.

FIG. 6 shows a proportion of nonalcoholic liver disease in carriers and non-carriers of CIDEB rare coding variants across body mass index categories. The percentage of non-alcoholic liver disease is shown for carriers vs non-carriers of rare coding CIDEB variants, stratified by body mass index. Panel a shows carriers of only pLOF variants, and Panel b shows carriers of pLOF and missense variants. Abbreviations: BMI, body mass index; pLOF, predicted loss of function; AAF, alternate allele frequency. Numbers above each bar represents the observed sample size within the group being represented by the bar.

FIG. 7 shows a visualization of the interaction between rare coding variants in CIDEB with PNPLA3 Ile148Met. Panel a shows the interaction of CIDEB genotype (i.e., rare pLOF variants) and Ile148Met on alanine aminotransferase level. Panel b shows the interaction of CIDEB genotype (i.e., rare pLOF and missense variants) and Ile148Met on alanine aminotransferase level. Abbreviations: pLOF, predicted loss of function; SD, standard deviation; P, p-value; ALT, alanine aminotransferase; BMI, body mass index; U/L, units per liter.

FIG. 8 shows CIDEB expression patterns across tissues (Panel a) and liver cell-types (Panel b). Panel a shows, per tissue, the normalized mRNA expression values for CIDEB in counts per million (CPM) for each individual using data from genotype tissue expression (GTEx) consortium (GTEx Portal 2021. Accessed 2021, June 1st via the world wide web at gtexportal.org/). Panel b shows normalized cell-type specific expression levels within liver, in transcripts per million protein coding genes (pTPM), obtained from the human protein atlas (HPA) (Nat. Biotechnol., 2010, 28, 1248-50). Box plots depict the median (thick black vertical bar), the interquartile range, and minimum and maximum CPM values across individuals per tissue.

FIG. 9 shows rare pLOF variants in CIDEB impart a loss-of-function via defective mRNA processing in the liver. Panel a shows the level of mRNA expression of CIDEB in liver of bariatric surgery patients from GHS (left), that of two Lys153* heterozygous carriers (middle) and that of two c.336+1G>A heterozygous carriers (right). Panel b shows allele-specific expression results for the two Lys153* heterozygous carriers in RNA sequence reads mapped to the variant site (left; dashed red lines indicate variant site and arrows indicate rare instances where the reads carry the mutant allele) and in a comparison of read counts with or without the mutant allele (right). Panel c shows allele-specific expression results for the two c.336+1G>A heterozygous carriers. The left panel shows RNA sequence reads mapped to the variant site (dashed red lines indicate variant site and arrows indicate rare instances where the reads carry the mutant allele). The middle panel shows the number of spliced and unspliced reads in the two carriers, with unspliced reads being the less frequent occurrence. The right panel shows the allele-specific expression in unspliced reads, which disproportionally carried the variant allele. Abbreviations: pLOF, predicted loss of function; CPM, counts per million; P, p-value; mRNA, mature messenger RNA.

FIG. 10 shows siRNA-mediated knockdown of CIDEB prevents lipid droplet build-up in HepG2 cells. Panel A shows intracellular localization of endogenous CIDEB to the interface of lipid droplets via immunofluorescent staining under basal conditions (no oleic acid) or in the presence of 400 μM oleic acid. Panel B shows the CIDEB protein staining is detectable in cells treated with control siRNA (top) but not CIDEB siRNA (bottom), demonstrating specificity of the CIDEB antibody used in both basal conditions (left) and oleic acid treatment (right). Purple, antibody staining of CIDEB; green, neutral lipids stained by BODIPY; blue, nuclei stained by DAPI; scale bar, 10 μm. Panel C shows western blot analysis (left and center) of CIDEB protein expression and Taqman analysis of CIDEB mRNA expression (right) in control or CIDEB siRNA-treated HepG2 cells. Data are presented as mean±s.d of independent wells and Welch's t-test was performed to determine statistical significance where * represents p<0.05. Panel D shows representative images of oleic acid treatment and CIDEB siRNA impact on lipid droplet size and distribution. Red, neutral lipids stained by AdipoRed; blue, nuclei stained by DAPI; scale bar, 20 μm. Panels E, F, and H show quantification of imaging-derived lipid droplet characteristics, barplots show mean±s.d. of 4 independent wells, depicted as individual points, per condition. Panel E shows the average number of lipid droplets per cell; Panel F shows the average lipid droplet size (quantified from the three-dimensional volume of individual lipid droplets); Panel H shows the average cell lipid droplet staining (quantified as the total area of lipid droplet staining in each cell). Panel G shows average triglyceride concentration per cell quantified using an enzymatic assay; data are mean±s.d of nine independent wells, depicted as individual points, per condition. Panel I shows concentrated of proinflammatory cytokine IL-8 secreted into the cell media quantified by immunoassay; data are mean±s.d. Differences in E-I were assessed using a two-way ANOVA; Tukey's multiple comparisons tests with Sidak correction were used to assess pairwise comparisons of CIDEB siRNA or oleic acid treatment (ns, not significant; * p<0.05; ** p<0.01; *** p<0.001; **** p<0.0001). Panel J shows AdipoRed staining of neutral lipids demonstrating increasing concentrations of oleic acid result in a dose-dependent increase lipid droplet size and cell lipid droplet staining (left). CIDEB siRNA pretreatment reduces the size of lipid droplets relative to control siRNA pretreatment (right). Red, neutral lipids stained by AdipoRed; blue, nuclei stained by 4′,6-diamidino-2-phenylindole (DAPI); scale bar, 20 μm. Abbreviations: DAPI, 4′,6-diamidino-2-phenylindole; OA, oleic acid; LD, lipid droplet.

DESCRIPTION

Various terms relating to aspects of the present disclosure are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art, unless otherwise indicated. Other specifically defined terms are to be construed in a manner consistent with the definitions provided herein.

Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is in no way intended that an order be inferred, in any respect. This holds for any possible non-expressed basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

As used herein, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.

As used herein, the term “about” means that the recited numerical value is approximate and small variations would not significantly affect the practice of the disclosed embodiments. Where a numerical value is used, unless indicated otherwise by the context, the term “about” means the numerical value can vary by ±10% and remain within the scope of the disclosed embodiments.

As used herein, the term “comprising” may be replaced with “consisting” or “consisting essentially of” in particular embodiments as desired.

As used herein, the terms “nucleic acid”, “nucleic acid molecule”, “nucleic acid sequence”, “polynucleotide”, or “oligonucleotide” can comprise a polymeric form of nucleotides of any length, can comprise DNA and/or RNA, and can be single-stranded, double-stranded, or multiple stranded. One strand of a nucleic acid also refers to its complement.

As used herein, the term “subject” includes any animal, including mammals. Mammals include, but are not limited to, farm animals (such as, for example, horse, cow, pig), companion animals (such as, for example, dog, cat), laboratory animals (such as, for example, mouse, rat, rabbits), and non-human primates (such as, for example, apes and monkeys). In some embodiments, the subject is a human. In some embodiments, the subject is a patient under the care of a physician.

It has been observed in accordance with the present disclosure that a gene burden of particular CIDEB variations (i.e., CIDEB variant nucleic acid molecules) associate with a decreased risk of developing a liver disease. It is believed that variants in CIDEB genes or proteins have not been significantly associated with liver disease or markers of liver damage in previous exome-sequencing association studies. Therefore, it is believed that humans having a liver disease or at risk of developing a liver disease may be treated with CIDEB inhibitors. Accordingly, the present disclosure provides methods for leveraging the identification of subjects who do not have such protective CIDEB variant nucleic acid molecules who, thus, are at risk of developing a liver disease, and to stratify the risk in such subjects of developing liver disease, such that subjects at risk or subjects with active disease may be treated with CIDEB inhibitors.

In any of the embodiments described herein, the CIDEB variant nucleic acid molecules can be any CIDEB nucleic acid molecule (such as, for example, genomic nucleic acid molecule, mRNA molecule, or cDNA molecule) encoding a CIDEB polypeptide having a partial loss-of-function, a complete loss-of-function, a predicted partial loss-of-function, or a predicted complete loss-of-function, or encoding a missense polypeptide, or resulting in the absence of an encoded polypeptide, or having an impact on the CIDEB mRNA sequence or expression. For example, the CIDEB variant nucleic acid molecules can be any of the CIDEB variant nucleic acid molecules described herein. A CIDEB variant nucleic acid molecule can be a variant that is predicted to result in the premature truncation of the CIDEB polypeptide (including, but not limited to, frameshift mutations, insertions or deletions, stop-gain, stop-lost, start-lost, splice site variants or large chromosomal or sub-chromosomal re-arrangements affecting the CIDEB gene). CIDEB variant nucleic acid molecules can include, but are not limited, to in-frame insertions or deletions in the CIDEB gene or variants in the untranslated regions of the CIDEB gene. A missense variant is a variant predicted to result in the change of an amino acid sequence of the CIDEB polypeptide.

For purposes of the present disclosure, any particular subject, such as a human, can be categorized as having one of three CIDEB genotypes: i) CIDEB reference; ii) heterozygous for a CIDEB variant nucleic acid molecule, and iii) homozygous for a CIDEB variant nucleic acid molecule. A subject is CIDEB reference when the subject does not have a copy of a CIDEB variant nucleic acid molecule. A subject is heterozygous for a CIDEB variant nucleic acid molecule when the subject has a single copy of a CIDEB variant nucleic acid molecule. A CIDEB variant nucleic acid molecule is any CIDEB nucleic acid molecule (such as, a genomic nucleic acid molecule, an mRNA molecule, or a cDNA molecule) encoding a CIDEB polypeptide having a partial loss-of-function, a complete loss-of-function, a predicted partial loss-of-function, or a predicted complete loss-of-function, or encoding a missense polypeptide, or having an impact on the CIDEB mRNA sequence. A subject who has a CIDEB polypeptide having a partial loss-of-function (or predicted partial loss-of-function, or a missense) is hypomorphic for CIDEB (lower abundance or function of the gene compared to the reference sequence version). The CIDEB variant nucleic acid molecule can be any variant nucleic acid molecule described herein. A subject is homozygous for a CIDEB variant nucleic acid molecule when the subject has two copies of any of the CIDEB variant nucleic acid molecules.

For subjects that are genotyped or determined to be heterozygous or homozygous for a CIDEB variant nucleic acid molecule, such subjects have a decreased risk of developing a liver disease compared to CIDEB reference subjects. For subjects that are genotyped or determined to be CIDEB reference, such subjects have an increased risk of developing a liver disease compared to carriers of the aforementioned CIDEB variants. For subjects that are genotyped or determined to be CIDEB reference or are heterozygous for a CIDEB variant nucleic acid molecule, such subjects can be treated with one or more CIDEB inhibitors. Such subjects can also be treated with therapeutic agents used to treat a liver disease. For subjects that are genotyped or determined to be CIDEB reference or are heterozygous for a CIDEB variant nucleic acid molecule, such subjects can also be treated with a combination of a CIDEB inhibitor and a PNPLA3 inhibitor and/or an HSD17B13 inhibitor.

For subjects that are genotyped or determined to be CIDEB reference and are carriers of a PNPLA3 variant nucleic acid molecule encoding PNPLA3 Ile148Met or Ile144Met, such subjects have an increased risk of developing a liver disease compared to subjects who are either CIDEB reference or carriers of the aforementioned CIDEB variant types, but do not carry a PNPLA3 variant nucleic acid molecule encoding PNPLA3 Ile148Met or Ile144Met (PNPLA3 reference). For subjects that are genotyped or determined to be CIDEB reference or are heterozygous for a CIDEB variant nucleic acid molecule and to be carriers of a PNPLA3 variant nucleic acid molecule encoding PNPLA3 Ile148Met or Ile144Met, such subjects can be treated with a combination of one or more CIDEB inhibitors and/or one or more PNPLA3 inhibitors. Such subjects can also be treated with therapeutic agents used to treat a liver disease. Such subjects can also be treated with an HSD17B13 inhibitor.

For subjects that are genotyped or determined to be CIDEB reference and are carriers of a nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide, such subjects have an increased risk of developing a liver disease compared to subjects who are either CIDEB reference or heterozygous carriers of the aforementioned CIDEB variants, but do not carry a nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide. For subjects that are genotyped or determined to be CIDEB reference or are heterozygous for a CIDEB variant nucleic acid molecule and to be carriers of a nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide, such subjects can be treated with a combination of one or more CIDEB inhibitors and/or one or more HSD17B13 inhibitors. Such subjects can also be treated with therapeutic agents used to treat a liver disease. Such subjects can also be treated with a PNPLA3 inhibitor.

In any of the embodiments described herein, the CIDEB variant nucleic acid molecule can be any nucleic acid molecule (such as, for example, genomic nucleic acid molecule, mRNA molecule, or cDNA molecule) encoding a CIDEB polypeptide having a partial loss-of-function, a complete loss-of-function, a predicted partial loss-of-function, or a predicted complete loss-of-function, or encoding a missense polypeptide, or having an impact on the CIDEB mRNA sequence. In some embodiments, the CIDEB variant nucleic acid molecule is a variant that causes or is predicted to cause a nonsynonymous amino acid substitution in CIDEB and whose allele frequency is less than 1/100 alleles in the population from which the subject is selected. In some embodiments, the CIDEB variant nucleic acid molecule is any rare missense variant (allele frequency <1%; or 1 in 100 alleles) or any missense variant predicted or demonstrated to result in a change in CIDEB polypeptide sequence, folding, structure, abundance or function regardless of frequency, or any splice-site, stop-gain, start-loss, stop-loss, frameshift, or in-frame indel, or other frameshift CIDEB variant or any other variant predicted or demonstrated to result in a change in the amino acid sequence of the CIDEB polypeptide. In some embodiments, the subject has one or more of the following CIDEB variant nucleic acid molecules: 14:24305635:A:AGTAG, 14:24305641:A:C, 14:24305650:G:A, 14:24305657:C:A, 14:24305662:G:T, 14:24305667:T:C, 14:24305671:C:A, 14:24305671:C:G, 14:24305701:A:T, 14:24305709:C:T, 14:24305718:A:G, 14:24305721:T:C, 14:24305728:G:GGCCTT, 14:24305743:T:C, 14:24305948:T:C, 14:24305966:C:T, 14:24305974:T:C, 14:24305980:TCA:T, 14:24305988:C:T, 14:24306014:C:T, 14:24306034:A:C, 14:24306041:C:G, 14:24306044:G:A, 14:24306047:G:A, 14:24306051:T:G, 14:24306064:T:C, 14:24306074:A:G, 14:24306077:G:C, 14:24306082:A:G, 14:24306083:T:A, 14:24306095:G:A, 14:24306122:A:G, 14:24306134:C:G, 14:24306373:C:G, 14:24306379:T:C, 14:24306382:G:A, 14:24306383:G:T, 14:24306426:T:G, 14:24306437:C:G, 14:24306439:G:C, 14:24306442:A:G, 14:24306444:A:G, 14:24306457:C:T, 14:24306463:C:T, 14:24306469:C:T, 14:24306480:A:G, 14:24306486:A:C, 14:24306504:A:G, 14:24306519:A:G, 14:24307382:G:C, 14:24307405:A:G, 14:24307417:A:T, 14:24307421:T:A, 14:24307441:C:A, 14:24307444:A:C, 14:24307444:A:G, 14:24307450:C:CGCTG, 14:24307461:TG:T, 14:24307469:AG:A, 14:24307474:C:T, 14:24307475:A:G, 14:24307833:G:C, 14:24307851:T:TAC, 14:24306426:T:C, 14:24307849:G:C, 14:24307448:G:T, 14:24305671:C:T, 14:24305663:C:T, 14:24305686:C:G, 14:24307829:A:C, 14:24307818:CTGAG:C, 14:24307856:C:T, 14:24306423:T:C, 14:24306061:AC:A, 14:24307390:C:T, 14:24306382:G:T, 14:24306373:C:T, 14:24305733:T:C, 14:24307858:T:C, 14:24306387:C:T, 14:24305637:T:C, 14:24306062:C:T, 14:24307853:C:G, 14:24307450:C:G, 14:24306052:TG:T, 14:24305673:G:A, 14:24306043:C:T, 14:24307834:G:A, 14:24306417:C:T, 14:24307451:G:A, 14:24307436:A:C, 14:24305953:ACTTT:A, 14:24306489:G:T, 14:24307441:C:T, 14:24306375:C:T, 14:24305657:C:G, 14:24306427:C:T, 14:24306524:C:T, 14:24307516:C:A, 14:24307840:G:C, 14:24307501:A:G, 14:24305968:A:C, 14:24305986:C:T, 14:24307441:C:G, 14:24307459:G:T, 14:24306017:T:A, 14:24307424:G:A, 14:24306072:G:T, 14:24307423:C:T, 14:24307450:C:T, 14:24306420:G:A, 14:24307454:G:A, 14:24305653:C:T, 14:24307442:G:A, 14:24306002:C:T, 14:24306076:C:T, 14:24305664:C:T, 14:24305961:TG:T, 14:24305706:A:G, 14:24305946:C:T, 14:24306455:G:C, 14:24307468:G:A, 14:24307825:A:C, 14:24306110:G:A, 14:24305710:C:T, 14:24307483:C:T, 14:24306459:A:G, 14:24305754:C:T, 14:24305650:G:C, 14:24305691:C:T, 14:24306508:G:C, 14:24306039:G:T, 14:24306139:T:C, 14:24306391:T:C, 14:24306373:C:A, 14:24307498:C:T, 14:24307415:G:A, 14:24306138:CTG:C, 14:24307453:T:C, 14:24305692:G:A, 14:24305683:C:G, 14:24307484:G:A, 14:24307385:C:T, 14:24306519:A:T, 14:24307839:A:C, 14:24305965:C:T, 14:24305988:CAT:C, 14:24306087:C:G, 14:24307439:C:T, 14:24307477:A:C, 14:24306436:G:T, 14:24306507:A:G, 14:24307397:C:T, 14:24307495:G:A, 14:24306034:A:T, 14:24306013:G:A, 14:24307381:A:G, 14:24306383:G:C, 14:24305638:A:G, 14:24307420:G:A, 14:24306020:C:T, 14:24306470:A:C, 14:24307435:C:T, 14:24306469:C:G, 14:24306451:C:T, 14:24306403:G:A, 14:24307515:C:G, 14:24307489:A:G, 14:24307414:C:T, 14:24306483:A:G, 14:24305755:G:A, 14:24305766:C:T, 14:24306064:T:G, 14:24307516:C:G, 14:24305766:C:G, 14:24306489:G:A, 14:24306097:T:C, 14:24305763:T:G, 14:24307447:G:A, 14:24307402:G:A, 14:24305972:C:G, 14:24306423:T:G, 14:24305974:T:TG, 14:24307411:T:C, 14:24306121:T:C, 14:24307516:C:T, 14:24306424:C:T, 14:24306039:G:C, 14:24307853:C:A, 14:24306388:A:G, 14:24305990:T:C, 14:24307822:G:GT, 14:24305640:G:A, 14:24307418:T:C, 14:24305758:G:C, 14:24306131:C:T, 14:24305953:A:G, 14:24305730:C:A, 14:24306418:A:G, 14:24306059:AC:A, 14:24307842:G:A, 14:24307837:T:G, 14:24306095:G:T, 14:24306109:C:T, 14:24307822:G:A, 14:24306077:G:A, 14:24307824:A:T, 14:24306080:C:T, 14:24305649:C:T, 14:24306433:G:GA, 14:24306420:G:C, 14:24305658:T:G, 14:24306472:C:T, 14:24307412:TC:T, 14:24306062:C:A, 14:24306044:G:C, 14:24306047:G:T, 14:24306126:CAG:C, 14:24306449:C:G, 14:24307391:G:A, or 14:24307857:A:C (according to GRCh38/hg38 human genome assembly coordinates).

In any of the embodiments described herein, the CIDEB variant nucleic acid molecules have one or more variations at the indicated positions of chromosome 14 using the nucleotide sequence of the CIDEB reference genomic nucleic acid molecule (SEQ ID NO:1; ENSG00000136305.11 in the GRCh38/hg38 human genome assembly, for which position 24,311,422 of chromosome 14 is the first nucleotide in SEQ ID NO:1).

In any of the embodiments described herein, the CIDEB variant nucleic acid molecules can be mRNA and cDNA molecules having the corresponding variant positions referring to the reference genomic sequence as a reference sequence.

The nucleotide sequences of CIDEB reference mRNA molecules produced through alternative splicing are set forth in SEQ ID NOs:2-12. The variant nucleotides at their respective variant positions for the variant genomic nucleic acid molecules described herein also have corresponding variant nucleotides at their respective variant positions for the variant mRNA molecules based upon the CIDEB reference mRNA sequences according to SEQ ID NOs:2-12. Any of these CIDEB variant mRNA molecules can be detected in any of the methods described herein.

The nucleotide sequences of CIDEB reference cDNA molecules produced through alternative splicing are set forth in SEQ ID NOs:13-23. The variant nucleotides at their respective variant positions for the variant genomic nucleic acid molecules described herein also have corresponding variant nucleotides at their respective variant positions for the variant cDNA molecules based upon the CIDEB reference cDNA sequences according to SEQ ID NOs:13-23. Any of these CIDEB variant cDNA molecules can be detected in any of the methods described herein.

The amino acid sequence of a CIDEB reference polypeptide is set forth in SEQ ID NO:24. Using the translated nucleotide sequence of either the CIDEB mRNA or cDNA molecules, the CIDEB variant polypeptides have corresponding translated variant amino acids at variant positions. Any of these CIDEB predicted loss-of-function polypeptides can be detected in any of the methods described herein.

The nucleotide and amino acid sequences listed in the accompanying sequence listing are shown using standard letter abbreviations for nucleotide bases, and three-letter code for amino acids. The nucleotide sequences follow the standard convention of beginning at the 5′ end of the sequence and proceeding forward (i.e., from left to right in each line) to the 3′ end. Only one strand of each nucleotide sequence is shown, but the complementary strand is understood to be included by any reference to the displayed strand. The amino acid sequence follows the standard convention of beginning at the amino terminus of the sequence and proceeding forward (i.e., from left to right in each line) to the carboxy terminus.

As used herein, the phrase “corresponding to” or grammatical variations thereof when used in the context of the numbering of a particular nucleotide or nucleotide sequence or position refers to the numbering of a specified reference sequence when the particular nucleotide or nucleotide sequence is compared to a reference sequence. In other words, the residue (such as, for example, nucleotide or amino acid) number or residue (such as, for example, nucleotide or amino acid) position of a particular polymer is designated with respect to the reference sequence rather than by the actual numerical position of the residue within the particular nucleotide or nucleotide sequence. For example, a particular nucleotide sequence can be aligned to a reference sequence by introducing gaps to optimize residue matches between the two sequences. In these cases, although the gaps are present, the numbering of the residue in the particular nucleotide or nucleotide sequence is made with respect to the reference sequence to which it has been aligned. A variety of computational algorithms exist that can be used for performing a sequence alignment to identify a nucleotide or amino acid position in one polymeric molecule that corresponds to a nucleotide or amino acid position in another polymeric molecule. For example, by using the NCBI BLAST algorithm (Altschul et al., Nucleic Acids Res., 1997, 25, 3389-3402) or CLUSTALW software (Sievers and Higgins, Methods Mol. Biol., 2014, 1079, 105-116) sequence alignments may be performed. However, sequences can also be aligned manually.

Any one or more (i.e., any combination) of the variants recited herein can be used within any of the methods described herein to determine whether a subject has an increased or decreased risk of developing a liver disease. The combinations of particular variants can form a gene-burden or “mask” used for statistical analysis of the particular correlation of CIDEB and higher or lower risk of developing a liver disease or liver damage (e.g., as quantified by liver biomarkers or imaging related variables).

In any of the embodiments described herein, the CIDEB predicted loss-of-function polypeptide can be any CIDEB polypeptide having a partial loss-of-function, a complete loss-of-function, a predicted partial loss-of-function, or a predicted complete loss-of-function, or missense polypeptide.

In any of the embodiments described herein, the liver disease is a fatty liver disease (such as, for example, alcoholic fatty liver disease (AFLD), non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH)), liver cirrhosis, liver fibrosis, an increased liver enzyme (such as, for example, alanine transaminase (ALT) or aspartate transaminase (AST)), simple steatosis, steatohepatitis, parenchymal liver disease, viral hepatitis, or hepatocellular carcinoma, or any of the complications of such conditions (including, but not limited to, heart or metabolic disease related to NASH or NAFLD, portal vein hypertension or thrombosis, esophageal or gastric varices or bleeding from those varices, and other liver-disease related co-morbidities). In some embodiments, the liver disease is a fatty liver disease. In some embodiments, the liver disease is AFLD. In some embodiments, the liver disease is NAFLD. In some embodiments, the liver disease is NASH. In some embodiments, the liver disease is liver cirrhosis. In some embodiments, the liver disease is liver fibrosis. In some embodiments, the liver disease is an increased liver enzyme. In some embodiments, the liver disease is increased ALT. In some embodiments, the liver disease is increased AST. In some embodiments, the liver disease is simple steatosis. In some embodiments, the liver disease is steatohepatitis. In some embodiments, the liver disease is parenchymal liver disease. In some embodiments, the liver disease is viral hepatitis. In some embodiments, the liver disease is hepatocellular carcinoma. In some embodiments, the liver disease is liver damage quantified by a liver biomarker (e.g., liver transaminase), a change in a liver biomarker, by liver imaging, or by liver histology.

Symptoms of liver disease include, but are not limited to, enlarged liver, fatigue, pain in the upper right abdomen, abdominal swelling (ascites), enlarged blood vessels just beneath the skin's surface, enlarged breasts in men, enlarged spleen, red palms, and yellowing of the skin and eyes (jaundice), pruritus, dark urine color, pale stool color nausea or vomiting, loss of appetite, and tendency to bruise easily. Testing for liver diseases can involve blood tests, imaging of the liver, and biopsy of the liver. An individual is at increased risk of a liver disease if the subject has at least one known risk-factor (e.g., genetic factor such as a disease-causing mutation) placing individuals with that risk factor at a statistically significant greater risk of developing the disease than individuals without the risk factor. Risk factors for liver diseases are also well known and can include, for example, excessive alcohol use, obesity, high cholesterol, high levels of triglycerides in the blood, polycystic ovary syndrome, sleep apnea, type 2 diabetes, underactive thyroid (hypothyroidism), underactive pituitary gland (hypopituitarism), and metabolic syndromes including raised blood lipids.

The present disclosure provides methods of treating a subject having a liver disease or at risk of developing a liver disease, the methods comprising administering a CIDEB inhibitor to the subject.

The present disclosure also provides methods of treating a subject having a liver disease or at risk of developing a liver disease, wherein the subject is heterozygous or homozygous for a nucleic acid molecule encoding PNPLA3 Ile148Met or Ile144Met, the methods comprising administering: i) a CIDEB inhibitor in an amount that is the same as or greater than a standard dosage amount; ii) a combination of a CIDEB inhibitor in an amount that is the same as or greater than a standard dosage amount and a PNPLA3 inhibitor; iii) a combination of a CIDEB inhibitor in an amount that is the same as or greater than a standard dosage amount and an HSD17B13 inhibitor; or iv) a combination of a CIDEB inhibitor in an amount that is the same as or greater than a standard dosage amount, aPNPLA3 inhibitor, and an HSD17B13 inhibitor.

The present disclosure also provides methods of treating a subject having a liver disease or at risk of developing a liver disease, wherein: when the subject is homozygous for a nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide, the subject is administered: i) a CIDEB inhibitor in an amount that is the same as or greater than a standard dosage amount; ii) a combination of a CIDEB inhibitor in an amount that is the same as or greater than a standard dosage amount and a PNPLA3 inhibitor; iii) a combination of a CIDEB inhibitor in an amount that is the same as or greater than a standard dosage amount and an HSD17B13 inhibitor; or iv) a combination of a CIDEB inhibitor in an amount that is the same as or greater than a standard dosage amount, aPNPLA3 inhibitor, and an HSD17B13 inhibitor; and when the subject is not homozygous for a nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide (i.e., is a carrier for a loss-of-function HSD17B13), the subject is administered: i) a CIDEB inhibitor in an amount that is less than a standard dosage amount; ii) a combination of a CIDEB inhibitor in an amount that is less than a standard dosage amount and a PNPLA3 inhibitor; iii) a combination of a CIDEB inhibitor in an amount that is less than a standard dosage amount and an HSD17B13 inhibitor; or iv) a combination of a CIDEB inhibitor in an amount that is less than a standard dosage amount, aPNPLA3 inhibitor, and an HSD17B13 inhibitor.

The present disclosure also provides methods of treating a subject having a liver disease or at risk of developing a liver disease, wherein the subject is heterozygous or homozygous for a nucleic acid molecule encoding a PNPLA3 Ile148Met or Ile144Met polypeptide and is heterozygous or homozygous for a nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide, the methods comprising administering a combination of a CIDEB inhibitor, a PNPLA3 inhibitor, and/or an HSD17B13 inhibitor to the subject.

In these methods, the subject can have any one or more of the liver diseases disclosed herein. In some embodiments, the liver disease is a fatty liver disease. In some embodiments, the liver disease is NAFLD or NASH. In some embodiments, the liver disease is NAFLD. In some embodiments, the liver disease is NASH. In some embodiments, the liver disease is liver cirrhosis. In some embodiments, the liver disease is fibrosis. In some embodiments, the liver disease is an increased liver enzyme. In some embodiments, the liver enzyme is ALT. In some embodiments, the liver enzyme is AST.

The present disclosure also provides methods of treating a subject having a liver disease or at risk of developing a liver disease, the methods comprising determining a nonalcoholic fatty liver disease (NAFLD) activity score (or NASH-CRN nonalcoholic fatty-liver disease activity score or NAS (NASH-CRN nonalcoholic fatty-liver disease activity score)), and when the NAFLD activity score is greater than a pre-determined score, administering to the subject a CIDEB inhibitor, a PNPLA3 inhibitor, or an HSD17B13 inhibitor, or any combination thereof, as described herein. The NAFLD activity score is defined by histological examinations from liver biopsies and scored based on the NASH Clinical Research Network system: steatosis Grade 0 (<5% parenchymal involvement), steatosis Grade 1 (5 to <34%), steatosis Grade 2 (34 to <67%), and steatosis Grade 3 (>67%); lobular inflammation Grade 0 (no foci), lobular inflammation Grade 1 (mild, <2 foci per 200× field), lobular inflammation Grade 2 (moderate, 2-4 foci per 200× field), lobular inflammation Grade 3 (severe, >4 foci per 200× field); ballooning Grade 0 (none), ballooning Grade 1 (few balloon cells), ballooning Grade 2 (many cells/prominent ballooning); fibrosis Stage 0 (none), fibrosis Stage 1 (perisinusoidal or periportal fibrosis), fibrosis Stage 2 (perisinusoidal and periportal fibrosis), fibrosis Stage 3 (bridging fibrosis), and fibrosis Stage 4 (cirrhosis). 5) Nonalcoholic fatty liver disease (NAFLD) activity score (NAS) defined as the unweighted sum of the scores for steatosis (0-3), lobular inflammation (0-3), and ballooning (0-2), thus ranging from 0-8. In some embodiments, the pre-determined NAFLD activity score is greater than 0. In some embodiments, the pre-determined NAFLD activity score is greater than 1. In some embodiments, the pre-determined NAFLD activity score is greater than 2. In some embodiments, the pre-determined NAFLD activity score is greater than 3. In some embodiments, the pre-determined NAFLD activity score is greater than 4. In some embodiments, the pre-determined NAFLD activity score is greater than 5.

In some embodiments, the CIDEB inhibitor comprises an inhibitory nucleic acid molecule. Examples of inhibitory nucleic acid molecules include, but are not limited to, antisense nucleic acid molecules, small interfering RNAs (siRNAs), and short hairpin RNAs (shRNAs). Such inhibitory nucleic acid molecules can be designed to target any region of a CIDEB mRNA. In some embodiments, the antisense RNA, siRNA, or shRNA hybridizes to a sequence within a CIDEB genomic nucleic acid molecule or mRNA molecule and decreases expression of the CIDEB polypeptide in a cell in the subject. In some embodiments, the CIDEB inhibitor comprises an antisense RNA that hybridizes to a CIDEB genomic nucleic acid molecule or mRNA molecule and decreases expression of the CIDEB polypeptide in a cell in the subject. In some embodiments, the CIDEB inhibitor comprises an siRNA that hybridizes to a CIDEB genomic nucleic acid molecule or mRNA molecule and decreases expression of the CIDEB polypeptide in a cell in the subject. In some embodiments, the CIDEB inhibitor comprises an shRNA that hybridizes to a CIDEB genomic nucleic acid molecule or mRNA molecule and decreases expression of the CIDEB polypeptide in a cell in the subject.

The inhibitory nucleic acid molecules described herein can be targeted to various CIDEB transcripts. For example, the inhibitory nucleic acid molecules described herein can be targeted to the CIDEB transcripts (derived from chromosome 14; Ensembl Gene ID=ENSG00000136305; hgnc symbol=CIDEB; from top to bottom=Transcript A, Transcript B, Transcript C, Transcript D, Transcript E, and Transcript F) in Table 1.

TABLE 1 Ensembl Transcript Transcript Transcript id Start End Name Coordinates Length ENST00000258807 24305187 24311422 CIDEB_258807 chr14: 24311422- 6235 24305187 ENST00000336557 24305187 24311395 CIDEB_336557 chr14: 24311395- 6208 24305187 ENST00000554411 24305096 24308263 CIDEB_554411 chr14: 24308263- 3167 24305096 ENST00000555471 24310087 24310718 CIDEB_555471 chr14: 24310718- 631 24310087 ENST00000555817 24310799 24311430 CIDEB_555817 chr14: 24311430- 631 24310799 ENST00000556756 24305606 24306461 CIDEB_556756 chr14: 24306461- 855 24305606 Additional CIDEB transcripts include, but are not limited to those of the following Ensembl Gene IDs=ENST00000555471, ENST00000555817, ENST00000556756, ENST00000258807, ENS100000336557, and ENST00000554411.

In some embodiments, the antisense nucleic acid molecules targeted to Transcript A comprise or consist of the nucleotide sequences shown in Table 2.

TABLE 2 SEQ ID Sequence NO: ACCACGCAGUCAACCUUCUG  115 UACCACGCAGUCAACCUUCU  116 CUACCACGCAGUCAACCUUC  117 CCUACCACGCAGUCAACCUU  118 CCCUACCACGCAGUCAACCU  119 UUGCCUUCGGCUUGCUCUGG  120 CUUGCCUUCGGCUUGCUCUG  121 GCUUGCCUUCGGCUUGCUCU  122 UGCUUGCCUUCGGCUUGCUC  123 GUGCUUGCCUUCGGCUUGCU  124 UCGUGCUUGCCUUCGGCUUG  125 AUCGUGCUUGCCUUCGGCUU  126 CAUCGUGCUUGCCUUCGGCU  127 AGCGCCAUCGUGCUUGCCUU  128 UGGUGAGCGCCAUCGUGCUU  129 CUGAUGCUCGGCUGCUACAG  130 GCUGAUGCUCGGCUGCUACA  131 UUUCGGGCUGAUGCUCGGCU  132 UCCUUUCGGGCUGAUGCUCG  133 UUCCUUUCGGGCUGAUGCUC  134 CUUCCUUUCGGGCUGAUGCU  135 GCUUCCUUUCGGGCUGAUGC  136 UGCUUCCUUUCGGGCUGAUG  137 GUGCUUCCUUUCGGGCUGAU  138 CGUGCUUCCUUUCGGGCUGA  139 UCGUGCUUCCUUUCGGGCUG  140 UUCGUGCUUCCUUUCGGGCU  141 UUUCGUGCUUCCUUUCGGGC  142 CUUUCGUGCUUCCUUUCGGG  143 GCUUUCGUGCUUCCUUUCGG  144 AUGUACGCCAGCGUGCUGCU  145 UCAGCAUGUACGCCAGCGUG  146 AGGCGGUGUACUACGUGUGC  147 AAGGCGGUGUACUACGUGUG  148 CAAGGCGGUGUACUACGUGU  149 GCAAGGCGGUGUACUACGUG  150 UGCAAGGCGGUGUACUACGU  151 CUGCAAGGCGGUGUACUACG  152 GCUGCAAGGCGGUGUACUAC  153 GGCUGCAAGGCGGUGUACUA  154 GCUCUUUGUGGCCUUCCUGA  155 CGCUCUUUGUGGCCUUCCUG  156 CUUCGUGGUGUGGAGCUUGG  157 GGCUUCGUGGUGUGGAGCUU  158 CAACGGCUUCGUGGUGUGGA  159 UGGCAACGGCUUCGUGGUGU  160 UGAGCUGGAAGACUUCGCGG  161 CUGAGCUGGAAGACUUCGCG  162 GCUGAGCUGGAAGACUUCGC  163 ACACUGCUGAGCUGGAAGAC  164 CGAGACACUGCUGAGCUGGA  165 ACGAGACACUGCUGAGCUGG  166 AACGAGACACUGCUGAGCUG  167 GAACGAGACACUGCUGAGCU  168 GGAACGAGACACUGCUGAGC  169 GGGAACGAGACACUGCUGAG  170 AGGGAACGAGACACUGCUGA  171 CAGGGAACGAGACACUGCUG  172 CCAGGGAACGAGACACUGCU  173 AAGGAUGUCGGUCUGCUACC  174 GAAGGAUGUCGGUCUGCUAC  175 AGAAGGAUGUCGGUCUGCUA  176 UAGGCCCAGAAGGAUGUCGG  177 GUAGGCCCAGAAGGAUGUCG  178 UGUAGGCCCAGAAGGAUGUC  179 CUGUAGGCCCAGAAGGAUGU  180 CCUGUAGGCCCAGAAGGAUG  181 ACCUGUAGGCCCAGAAGGAU  182 CUUCUCAUCGGGCAUCACAG  183 CCUUCUCAUCGGGCAUCACA  184 ACCUUCUCAUCGGGCAUCAC  185 CACCUUCUCAUCGGGCAUCA  186 GCACCUUCUCAUCGGGCAUC  187 GGCACCUUCUCAUCGGGCAU  188 UGGCACCUUCUCAUCGGGCA  189 AUGGCACCUUCUCAUCGGGC  190 CAUGGCACCUUCUCAUCGGG  191 GCAUGGCACCUUCUCAUCGG  192 GGCAUGGCACCUUCUCAUCG  193 GAGGCAUGGCACCUUCUCAU  194 GGAGGCAUGGCACCUUCUCA  195 GACUCCCAGGCAGAAAAGAG  196 GGACUCCCAGGCAGAAAAGA  197 AGGACUCCCAGGCAGAAAAG  198 UCAGGACUCCCAGGCAGAAA  199 GAAGUCAGGACUCCCAGGCA  200 GUGGAAGUCAGGACUCCCAG  201 UCGUGGAAGUCAGGACUCCC  202 CUCGUGGAAGUCAGGACUCC  203 CCUCGUGGAAGUCAGGACUC  204 UGGGUCCUCGUGGAAGUCAG  205 CUGGGUCCUCGUGGAAGUCA  206 UCUGGGUCCUCGUGGAAGUC  207 GUCUGGGUCCUCGUGGAAGU  208 AAGAAGGAGUUGUGUUUGAG  209 CCAAGAAGGAGUUGUGUUUG  210 GUUCCAAGAAGGAGUUGUGU  211 GGUUCCAAGAAGGAGUUGUG  212 CAGGUCAACUGACUGGGAGC  213 UGCCUGUUUACCACUGAGCU  214 AUGCCUGUUUACCACUGAGC  215 UAUGCCUGUUUACCACUGAG  216 UUAUGCCUGUUUACCACUGA  217 UUUAUGCCUGUUUACCACUG  218 CUUUAUGCCUGUUUACCACU  219 ACUUUAUGCCUGUUUACCAC  220 UAGAGAUAGUGACAGCCUGG  221 GUAGAGAUAGUGACAGCCUG  222 UGGUGGUAGAGAUAGUGACA  223 GUGGUGGUAGAGAUAGUGAC  224 UAGAGGAGUGGUGGUAGAGA  225 ACUAGAGGAGUGGUGGUAGA  226 AGACUAGAGGAGUGGUGGUA  227 CAGACUAGAGGAGUGGUGGU  228 CCAGACUAGAGGAGUGGUGG  229 GCCAGACUAGAGGAGUGGUG  230 GGCCAGACUAGAGGAGUGGU  231 GCCCAGAUGUGCUAGAAUGG  232 UGCCCAGAUGUGCUAGAAUG  233 UUGCCCAGAUGUGCUAGAAU  234 UUUGCCCAGAUGUGCUAGAA  235 UUUUGCCCAGAUGUGCUAGA  236 CCAGUUUUGCCCAGAUGUGC  237 AUCCAGUUUUGCCCAGAUGU  238 CCAUCCAGUUUUGCCCAGAU  239 CACCAUCCAGUUUUGCCCAG  240 CCACCAUCCAGUUUUGCCCA  241 CCCACCAUCCAGUUUUGCCC  242 UUGCUCCCAGCUUGGUAAGU  243 GCUUGCUCCCAGCUUGGUAA  244 AUCCUGCUUGCUCCCAGCUU  245 AAUCCUGCUUGCUCCCAGCU  246 CAAUCCUGCUUGCUCCCAGC  247 CCAAUCCUGCUUGCUCCCAG  248 AACCUUUCAGCUUCUCCAGG  249 UAACCUUUCAGCUUCUCCAG  250 UUAACCUUUCAGCUUCUCCA  251 ACUGCUGCUUAACCUUUCAG  252 UACUGCUGCUUAACCUUUCA  253 CUACUGCUGCUUAACCUUUC  254 CCUACUGCUGCUUAACCUUU  255 GCCUACUGCUGCUUAACCUU  256 CAGGACAGGAGUAGGCACCU  257 ACAGGACAGGAGUAGGCACC  258 GCACAGGACAGGAGUAGGCA  259 AUAGGCACAGGACAGGAGUA  260 GAUAGGCACAGGACAGGAGU  261 UGAUAGGCACAGGACAGGAG  262 ACCCUCUGCAAAUGUGAUAG  263 CUUACCCUCUGCAAAUGUGA  264 GUCUUACCCUCUGCAAAUGU  265 UGUCUUACCCUCUGCAAAUG  266 UUGUCUUACCCUCUGCAAAU  267 CUUGUCUUACCCUCUGCAAA  268 UCUUGUCUUACCCUCUGCAA  269 CAUUCUUGUCUUACCCUCUG  270 CCCAUUCUUGUCUUACCCUC  271 GAGCCUCAUCUUGUCCCUCC  272 UGAGCCUCAUCUUGUCCCUC  273 UGCGUUGGUGAUGGGAAGGA  274 GUGCGUUGGUGAUGGGAAGG  275 GGUGCGUUGGUGAUGGGAAG  276 GGGUGCGUUGGUGAUGGGAA  277 UGGGUGCGUUGGUGAUGGGA  278 UCUCACAUGCCUGGACGCCU  279 CAAGGCAGGCUCUCACAUGC  280 UGCUGUUUCCUGGCAAGGCA  281 UUGUGCUGUUUCCUGGCAAG  282 CUUGUGCUGUUUCCUGGCAA  283 ACCACCAGGGAAUCUUACUG  284 UCCACCACCAGGGAAUCUUA  285 AUUUCCUUCCACCACCAGGG  286 UAUUUCCUUCCACCACCAGG  287 CCUAUUUCCUUCCACCACCA  288 AGUCCUCCUAUUUCCUUCCA  289 AGAGUCCUCCUAUUUCCUUC  290 AGCAGAGUCCUCCUAUUUCC  291 CAGCAGAGUCCUCCUAUUUC  292 AUUCAGCAGAGUCCUCCUAU  293 ACCAGGAUUCAGCAGAGUCC  294 GACCAGGAUUCAGCAGAGUC  295 GGACCAGGAUUCAGCAGAGU  296 CAGGACCAGGAUUCAGCAGA  297 CAGAAGCAGGACCAGGAUUC  298 ACAGAAGCAGGACCAGGAUU  299 AACAGAAGCAGGACCAGGAU  300 AGAACAGAAGCAGGACCAGG  301 GGGAGGGAUGAGAACAGAAG  302 CAGGCAACAUACACACUGCA  303 CCAGGCAACAUACACACUGC  304 ACCAGGCAACAUACACACUG  305 AGACCAGGCAACAUACACAC  306 GAGAGACCAGGCAACAUACA  307 CCAGAGAGACCAGGCAACAU  308 UUGUUUGGGUCACCUCUGCA  309 GUUGUUUGGGUCACCUCUGC  310 AGUUGUUUGGGUCACCUCUG  311 UGAGUUGUUUGGGUCACCUC  312 CUGAGUUGUUUGGGUCACCU  313 GACUGAGUUGUUUGGGUCAC  314 AAACAGGCAAGGAUAAGGCA  315 ACAUGGAAAAGCUGUCAUUG  316 CCUUACAUGGAAAAGCUGUC  317 GCCUUACAUGGAAAAGCUGU  318 CUCCUGGAACCUAGCACCAU  319 CCUCCUGGAACCUAGCACCA  320 UCCUCCUGGAACCUAGCACC  321 AACCAUUAUGCCUCCAUGCA  322 UAACCAUUAUGCCUCCAUGC  323 CUAACCAUUAUGCCUCCAUG  324 CCUAACCAUUAUGCCUCCAU  325 CCCUAACCAUUAUGCCUCCA  326 ACUCCCUAACCAUUAUGCCU  327 GACUCCCUAACCAUUAUGCC  328 UGACUCCCUAACCAUUAUGC  329 AUGACUCCCUAACCAUUAUG  330 CAUGACUCCCUAACCAUUAU  331 GGGCCUCUUCAUGGUUGUGU  332 UGGUGCAGCCUGGUAAUGGG  333 CUGGUGCAGCCUGGUAAUGG  334 CCUGGUGCAGCCUGGUAAUG  335 AUCCUGGUGCAGCCUGGUAA  336 UAUCCUGGUGCAGCCUGGUA  337 GUAUCCUGGUGCAGCCUGGU  338 UGUAUCCUGGUGCAGCCUGG  339 UCUUGUAUCCUGGUGCAGCC  340 GUCUUGUAUCCUGGUGCAGC  341 UGUCUUGUAUCCUGGUGCAG  342 UUGUCUUGUAUCCUGGUGCA  343 CUUGUCUUGUAUCCUGGUGC  344 UCUUGUCUUGUAUCCUGGUG  345 UUCUUGUCUUGUAUCCUGGU  346 UUUCUUGUCUUGUAUCCUGG  347 CCUUUCUUGUCUUGUAUCCU  348 ACUCAUCCUUUCCUUUCUUG  349 CCUACUCAUCCUUUCCUUUC  350 CCCUACUCAUCCUUUCCUUU  351 UCCCUACUCAUCCUUUCCUU  352 GCUUCUUAGUAUGUCCCUAC  353 GCUGCUUCUUAGUAUGUCCC  354 GGCUGCUUCUUAGUAUGUCC  355 GGGCUGCUUCUUAGUAUGUC  356 AGGGCUGCUUCUUAGUAUGU  357 GAGAGGGCUGCUUCUUAGUA  358 UCCAAGAGGAGAGGGCUGCU  359 UUGACUUUUCCAAGAGGAGA  360 AGCUCUAUCCAUCUGCCAGG  361 GCUGUUACUUGAGCAGAGGC  362 GGCUGUUACUUGAGCAGAGG  363 UGGCUGUUACUUGAGCAGAG  364 CUGGCUGUUACUUGAGCAGA  365 UCUGGCUGUUACUUGAGCAG  366 CCUCAAGUUCUGGCUGUUAC  367 ACCUCAAGUUCUGGCUGUUA  368 CAACCUCAAGUUCUGGCUGU  369 GCAACCUCAAGUUCUGGCUG  370 AGCAACCUCAAGUUCUGGCU  371 CAAGCAACCUCAAGUUCUGG  372 CCAAGCAACCUCAAGUUCUG  373 CCCAAGCAACCUCAAGUUCU  374 ACUAAGACAGUGCUCCUGGU  375 CAAACUAAGACAGUGCUCCU  376 AGCUCUGCUUUGGAAGAACC  377 CCCUUAGCUCAAGCUCUGCU  378 GCCCUUAGCUCAAGCUCUGC  379 AAGCCCUUAGCUCAAGCUCU  380 CAAGCCCUUAGCUCAAGCUC  381 CCAAGCCCUUAGCUCAAGCU  382 CCCAAGCCCUUAGCUCAAGC  383 GUACCCAAGCCCUUAGCUCA  384 UGUACCCAAGCCCUUAGCUC  385 CUGUACCCAAGCCCUUAGCU  386 CCUGUACCCAAGCCCUUAGC  387 ACCUGUACCCAAGCCCUUAG  388 UCACCUGUACCCAAGCCCUU  389 AUCACCUGUACCCAAGCCCU  390 GGAUCACCUGUACCCAAGCC  391 CUCAAGAAUACAGGAUCACC  392 CUUAGCUCAAGAAUACAGGA  393 CCUUAGCUCAAGAAUACAGG  394 GCCCUUAGCUCAAGAAUACA  395 AGCCCUUAGCUCAAGAAUAC  396 AAGCCCUUAGCUCAAGAAUA  397 CAAGCCCUUAGCUCAAGAAU  398 CCAAGCCCUUAGCUCAAGAA  399 CCCAAGCCCUUAGCUCAAGA  400 GUACCCAAGCCCUUAGCUCA  401 UGUACCCAAGCCCUUAGCUC  402 CUGUACCCAAGCCCUUAGCU  403 CCUGUACCCAAGCCCUUAGC  404 ACCUGUACCCAAGCCCUUAG  405 UCACCUGUACCCAAGCCCUU  406 AUCACCUGUACCCAAGCCCU  407 GGAUCACCUGUACCCAAGCC  408 UAACCUCCCAAAUACAGGAU  409 UACCUUAUGCCCUCACUUCC  410 UUACCUUAUGCCCUCACUUC  411 UUUACCUUAUGCCCUCACUU  412 UUUUACCUUAUGCCCUCACU  413 UUGUUUUACCUUAUGCCCUC  414 CUUGUUUUACCUUAUGCCCU  415 UUAAUGGCUUUCCUCUCUCU  416 ACUCUUAAUGGCUUUCCUCU  417 UACUCUUAAUGGCUUUCCUC  418 CAUACUCUUAAUGGCUUUCC  419 GAAGGGACUUAACAUACUCU  420 UGAAGGGACUUAACAUACUC  421 ACUGAAGGGACUUAACAUAC  422 CUACUGAAGGGACUUAACAU  423 GCCUACUGAAGGGACUUAAC  424 GGCCUACUGAAGGGACUUAA  425 UUCUCAGAGGUUCCCAAGGC  426 UUUUCUCAGAGGUUCCCAAG  427 ACUUUUCUCAGAGGUUCCCA  428 UACUUUUCUCAGAGGUUCCC  429 GGGCAAUCUAUACUUUUCUC  430 UGUCUUGGGCAAUCUAUACU  431 CCAGUCUUUUGUCUUGGGCA  432 GCCAGUCUUUUGUCUUGGGC  433 UGCCAGUCUUUUGUCUUGGG  434 CUGCCAGUCUUUUGUCUUGG  435 UCACCCUGCCAGUCUUUUGU  436 AUCACCCUGCCAGUCUUUUG  437 GCCCACUCAUUAAGUACAUU  438 CUGUAGCCCACUCAUUAAGU  439 CGCUGUAGCCCACUCAUUAA  440 ACGCUGUAGCCCACUCAUUA  441 UACGCUGUAGCCCACUCAUU  442 AUACGCUGUAGCCCACUCAU  443 GAUACGCUGUAGCCCACUCA  444 GGAUACGCUGUAGCCCACUC  445 AGGAUACGCUGUAGCCCACU  446 GAGGAUACGCUGUAGCCCAC  447 UGAGGAUACGCUGUAGCCCA  448 GUGAGGAUACGCUGUAGCCC  449 UGUGAGGAUACGCUGUAGCC  450 CUGUUGUGAGGAUACGCUGU  451 UCUGUUGUGAGGAUACGCUG  452 GUCUGUUGUGAGGAUACGCU  453 UGUCUGUUGUGAGGAUACGC  454 ACUGUCUGUUGUGAGGAUAC  455 CACUGUCUGUUGUGAGGAUA  456 CAACUCUCUCUCACUGUCUG  457 AACAACUCUCUCUCACUGUC  458 AGAACAACUCUCUCUCACUG  459 GUAGAACAACUCUCUCUCAC  460 GGUAGAACAACUCUCUCUCA  461 CAGGUAGAACAACUCUCUCU  462 CCAGGUAGAACAACUCUCUC  463 ACCCAGGUAGAACAACUCUC  464 UAUACCCAGGUAGAACAACU  465 AUAUACCCAGGUAGAACAAC  466 GGAUAUACCCAGGUAGAACA  467 GUUUUGGAUAUACCCAGGUA  468 CCUUGUUUUGGAUAUACCCA  469 CCCUUGUUUUGGAUAUACCC  470 CCUCGUAAACUCCAUACCCU  471 CCCUCGUAAACUCCAUACCC  472 ACCCUCGUAAACUCCAUACC  473 AACCCUCGUAAACUCCAUAC  474 GAACCCUCGUAAACUCCAUA  475 UGAACCCUCGUAAACUCCAU  476 UUGAACCCUCGUAAACUCCA  477 CUUGAACCCUCGUAAACUCC  478 CCUUGAACCCUCGUAAACUC  479 ACCUUGAACCCUCGUAAACU  480 UACCUUGAACCCUCGUAAAC  481 AUACCUUGAACCCUCGUAAA  482 AAUACCUUGAACCCUCGUAA  483 AAAUACCUUGAACCCUCGUA  484 CAAAUACCUUGAACCCUCGU  485 CCAAAUACCUUGAACCCUCG  486 ACCAAAUACCUUGAACCCUC  487 AACCAAAUACCUUGAACCCU  488 GAACCAAAUACCUUGAACCC  489 UGAACCAAAUACCUUGAACC  490 CCCUGAACCAAAUACCUUGA  491 GGCCCUGAACCAAAUACCUU  492 UGGCCCUGAACCAAAUACCU  493 UAUUCAGGUUGUUGCCCAAA  494 GGUAUUCAGGUUGUUGCCCA  495 AGGUAUUCAGGUUGUUGCCC  496 AAGGUAUUCAGGUUGUUGCC  497 AAAGGUAUUCAGGUUGUUGC  498 UAACUUGAUUGCCCUGUGAC  499 GUAACUUGAUUGCCCUGUGA  500 AGUAACUUGAUUGCCCUGUG  501 CAGAGUAACUUGAUUGCCCU  502 ACAGAGUAACUUGAUUGCCC  503 CACAGAGUAACUUGAUUGCC  504 UGUCCUGACAAAGAAACACA  505 CAAUCCCUGCUUUCCUGCCA  506 ACAAUCCCUGCUUUCCUGCC  507 AACACAAUCCCUGCUUUCCU  508 GAACACAAUCCCUGCUUUCC  509 AAUGAACACAAUCCCUGCUU  510 AAAUGAACACAAUCCCUGCU  511 GUGAAACCCUCAAAUGAACA  512 AGUGAAACCCUCAAAUGAAC  513 CAGUGAAACCCUCAAAUGAA  514 ACAGUGAAACCCUCAAAUGA  515 GCAUGGAAGCUGAGACUCUC  516 UUGCAUGGAAGCUGAGACUC  517 CAGUUGCAUGGAAGCUGAGA  518 ACAGUUGCAUGGAAGCUGAG  519 GACAGUUGCAUGGAAGCUGA  520 AUGGACAGUUGCAUGGAAGC  521 GUGAUGGACAGUUGCAUGGA  522 CGUGAUGGACAGUUGCAUGG  523 CCGUGAUGGACAGUUGCAUG  524 GCCGUGAUGGACAGUUGCAU  525 AGCCGUGAUGGACAGUUGCA  526 CAGCCGUGAUGGACAGUUGC  527 GCAGCCGUGAUGGACAGUUG  528 UGCAGCCGUGAUGGACAGUU  529 UUGCAGCCGUGAUGGACAGU  530 GUUGCAGCCGUGAUGGACAG  531 CAGUUGCAGCCGUGAUGGAC  532 UCAGUUGCAGCCGUGAUGGA  533 UUCAGUUGCAGCCGUGAUGG  534 UUUCAGUUGCAGCCGUGAUG  535 AUUUCAGUUGCAGCCGUGAU  536 GAUUUCAGUUGCAGCCGUGA  537 UGAUUUCAGUUGCAGCCGUG  538 CUCUGAUUUCAGUUGCAGCC  539 UUAGCUUCUGGUGCGCUGUG  540 UUUAGCUUCUGGUGCGCUGU  541 CUUUAGCUUCUGGUGCGCUG  542 GACUUUAGCUUCUGGUGCGC  543 AGACUUUAGCUUCUGGUGCG  544 AAGACUUUAGCUUCUGGUGC  545 UCAAGACUUUAGCUUCUGGU  546 AUCAAGACUUUAGCUUCUGG  547 GCAUCAAGACUUUAGCUUCU  548 AUGGCAUCAAGACUUUAGCU  549 GAUGGCAUCAAGACUUUAGC  550 AGGGAUGUCCUUUGAUGGCA  551 GCAGGGAUGUCCUUUGAUGG  552 GGCAGGGAUGUCCUUUGAUG  553 CGUGACAGAGAUGUGAAUGG  554 GGACGUGACAGAGAUGUGAA  555 UGGACGUGACAGAGAUGUGA  556 GUGGACGUGACAGAGAUGUG  557 AGUGGACGUGACAGAGAUGU  558 UAGUGGACGUGACAGAGAUG  559 UUAGUGGACGUGACAGAGAU  560 AUUAGUGGACGUGACAGAGA  561 GAUUAGUGGACGUGACAGAG  562 CGAUUAGUGGACGUGACAGA  563 CCGAUUAGUGGACGUGACAG  564 UGCCGAUUAGUGGACGUGAC  565 UUGCCGAUUAGUGGACGUGA  566 UUUGCCGAUUAGUGGACGUG  567 UUUUGCCGAUUAGUGGACGU  568 CUUUUGCCGAUUAGUGGACG  569 CCUUUUGCCGAUUAGUGGAC  570 UCCUUUUGCCGAUUAGUGGA  571 CUCCUUUUGCCGAUUAGUGG  572 UCUCCUUUUGCCGAUUAGUG  573 UUCUCCUUUUGCCGAUUAGU  574 UUUCUCCUUUUGCCGAUUAG  575 AGGUCAUCUUCUCUCACUUU  576 UUAGGUCAUCUUCUCUCACU  577 CUUAGGUCAUCUUCUCUCAC  578 ACACUUAGGUCAUCUUCUCU  579 CACACUUAGGUCAUCUUCUC  580 UCACACUUAGGUCAUCUUCU  581 GUCACACUUAGGUCAUCUUC  582 AGUCACACUUAGGUCAUCUU  583 CAGUCACACUUAGGUCAUCU  584 GCAGUCACACUUAGGUCAUC  585 UGCAGUCACACUUAGGUCAU  586 AUUUUCCAGAGCUGCCUGCU  587 CUCACUGCUCUGGCUUCAUU  588 GCUCACUGCUCUGGCUUCAU  589 UUACCUGCUCUUUCCUUCCU  590 UGCUUACCUGCUCUUUCCUU  591 UUCCUGCUUACCUGCUCUUU  592 CUUCCUGCUUACCUGCUCUU  593 ACUGGCCUUCCUGCUUACCU  594 GACACUGGCCUUCCUGCUUA  595 CAUUAGGGUCCUGUCUGGGA  596 UCAUUAGGGUCCUGUCUGGG  597 AUCAUUAGGGUCCUGUCUGG  598 GAUCAUUAGGGUCCUGUCUG  599 GGAUCAUUAGGGUCCUGUCU  600 AUUCAGGAUCAUUAGGGUCC  601 GAUUCAGGAUCAUUAGGGUC  602 GGAUUCAGGAUCAUUAGGGU  603 AUGGAUUCAGGAUCAUUAGG  604 GAUACAUGGAUUCAGGAUCA  605 UGAUACAUGGAUUCAGGAUC  606 AUGGCAGGGCUUUGGAAAAU  607 CAUGGCAGGGCUUUGGAAAA  608 GCAUGGCAGGGCUUUGGAAA  609 CAGCAUGGCAGGGCUUUGGA  610 GAAGUGGGAUGGCAGCAUGG  611 GGAAGUGGGAUGGCAGCAUG  612 GGGAAGUGGGAUGGCAGCAU  613 UGGAGAAGCCAUAAGCUGCA  614 CUGGAGAAGCCAUAAGCUGC  615 ACUGGAGAAGCCAUAAGCUG  616 UACUGGAGAAGCCAUAAGCU  617 CUACUGGAGAAGCCAUAAGC  618 CCUACUGGAGAAGCCAUAAG  619 ACCUACUGGAGAAGCCAUAA  620 CACCUACUGGAGAAGCCAUA  621 CCACCUACUGGAGAAGCCAU  622 GCCACCUACUGGAGAAGCCA  623 CUGCCACCUACUGGAGAAGC  624 GCUGCCACCUACUGGAGAAG  625 UGUGUGUGCUGCCACCUACU  626 CUGUGUGUGCUGCCACCUAC  627 UUAUGAGUGGCUCUGUGUGU  628 UUUAUGAGUGGCUCUGUGUG  629 AGUUUAUGAGUGGCUCUGUG  630 CAGUUUAUGAGUGGCUCUGU  631 GUUUCUGGCUCUCAGGCUCU  632 GGUUUCUGGCUCUCAGGCUC  633 CGGUUUCUGGCUCUCAGGCU  634 GGACGGUUUCUGGCUCUCAG  635 GGGACGGUUUCUGGCUCUCA  636 UGAAAUGUGACUUCUGGUGU  637 GGGAACCAUGUAAAAGGAUG  638 GUGAGGGUAGAUGGGAACCA  639 UUGUGAGGGUAGAUGGGAAC  640 GUUGUGAGGGUAGAUGGGAA  641 UGUUGUGAGGGUAGAUGGGA  642 AUGUGUGUCUUUGGUGAUGA  643 GGAGCUUGUAUGUGUGUCUU  644 UUGGAGCUUGUAUGUGUGUC  645 AUUGGAGCUUGUAUGUGUGU  646 CAUUGGAGCUUGUAUGUGUG  647 CCAUUGGAGCUUGUAUGUGU  648 GCCAUUGGAGCUUGUAUGUG  649 AGCCAUUGGAGCUUGUAUGU  650 CUGGAGGAAGAAUUGCCUGG  651 GUCCUGGAGGAAGAAUUGCC  652 GCCAGUAAGAAGGGCAAAGU  653 GGCCAGUAAGAAGGGCAAAG  654 GGAAUGAGUCAAGCCUGGAC  655 GGGAAUGAGUCAAGCCUGGA  656 GUGGGAAUGAGUCAAGCCUG  657 AAGGUGGGAAUGAGUCAAGC  658 UCUCAGCCCAGGACAAGGUG  659 AUCUCAGCCCAGGACAAGGU  660 GCUGGGUGGUUCUCUCCUGU  661 UUCUGGGCUGGGUGGUUCUC  662 GAACUUCUGGGCUGGGUGGU  663 CGGAGAGUUCCUUCCCUGGA  664 ACCGGAGAGUUCCUUCCCUG  665 GACCGGAGAGUUCCUUCCCU  666 UGGACCGGAGAGUUCCUUCC  667 GUGGACCGGAGAGUUCCUUC  668 GGUGGACCGGAGAGUUCCUU  669 UGGUGGACCGGAGAGUUCCU  670 AUGGUGGACCGGAGAGUUCC  671 CAUGGUGGACCGGAGAGUUC  672 GAGCUGAGAGGUACUCCAUG  673 AGAGCUGAGAGGUACUCCAU  674 CAGAGCUGAGAGGUACUCCA  675 UUCAGAGCUGAGAGGUACUC  676 GGUUCAGAGCUGAGAGGUAC  677 GGGUUCAGAGCUGAGAGGUA  678 CACCUGAGUAAGUCACUGGG  679 UCACCUGAGUAAGUCACUGG  680 GUCACCUGAGUAAGUCACUG  681 AGUCACCUGAGUAAGUCACU  682 CAGUCACCUGAGUAAGUCAC  683 GCAGUCACCUGAGUAAGUCA  684 UUAGCAGUCACCUGAGUAAG  685 GUUAGCAGUCACCUGAGUAA  686 GGUUAGCAGUCACCUGAGUA  687 GGGUUAGCAGUCACCUGAGU  688 AGGGUUAGCAGUCACCUGAG  689 GAGGGUUAGCAGUCACCUGA  690 GGAGGGUUAGCAGUCACCUG  691 CGGAGGGUUAGCAGUCACCU  692 AGCGGAGGGUUAGCAGUCAC  693 GAGCGGAGGGUUAGCAGUCA  694 AGAGCGGAGGGUUAGCAGUC  695 UAGAGCGGAGGGUUAGCAGU  696 GUAGAGCGGAGGGUUAGCAG  697 GGUAGAGCGGAGGGUUAGCA  698 AGGGUAGAGCGGAGGGUUAG  699 GAGGGUAGAGCGGAGGGUUA  700 AUUGUUGCCCUGCCUAUAUC  701 AGUAUUGUUGCCCUGCCUAU  702 GAGUAUUGUUGCCCUGCCUA  703 GGAGUAUUGUUGCCCUGCCU  704 UGGAGUAUUGUUGCCCUGCC  705 GUGGAGUAUUGUUGCCCUGC  706 AGUGGAGUAUUGUUGCCCUG  707 GAGUGGAGUAUUGUUGCCCU  708 UGAGUGGAGUAUUGUUGCCC  709 CUGAGUGGAGUAUUGUUGCC  710 GCUGAGUGGAGUAUUGUUGC  711 GGCUGAGUGGAGUAUUGUUG  712 GGGCUGAGUGGAGUAUUGUU  713 GGUACUGGUUAGUCUCCUAG  714 GGGUACUGGUUAGUCUCCUA  715 UUGACAAGCCCACUGUGGAG  716 UGGCUCAGGAGCUUGACAAG  717 GGUGGCUCAGGAGCUUGACA  718 UAGGGAUGAGGGAGAGACCA  719 UCGAUUAGGGAUGAGGGAGA  720 UAGAGGGCUAGGGAGGGAGA  721 GUAGAGUGGCUAGAGGGCUA  722 GGUAGAGUGGCUAGAGGGCU  723 UGAGGGUAGAGUGGCUAGAG  724 GAUGAGGGUAGAGUGGCUAG  725 CAUGAUGAGGGUAGAGUGGC  726 GCAUGAUGAGGGUAGAGUGG  727 GGGCAUGAUGAGGGUAGAGU  728 GGUAGUUGAGAAGAAAAGUC  729 CCAAACUCCGAGCUUAUAUU  730 UCCAAACUCCGAGCUUAUAU  731 GUCCAAACUCCGAGCUUAUA  732 CGUCCAAACUCCGAGCUUAU  733 CCGUCCAAACUCCGAGCUUA  734 UCCGUCCAAACUCCGAGCUU  735 CUCCGUCCAAACUCCGAGCU  736 ACCCUCCGUCCAAACUCCGA  737 AGACCCUCCGUCCAAACUCC  738 CAGACCCUCCGUCCAAACUC  739 UCCAGACCCUCCGUCCAAAC  740 GUCCAGACCCUCCGUCCAAA  741 AGACACGGAAAGGUCGCUGG  742 CAGACACGGAAAGGUCGCUG  743 ACAGACACGGAAAGGUCGCU  744 CACAGACACGGAAAGGUCGC  745 UCACAGACACGGAAAGGUCG  746 AUCACAGACACGGAAAGGUC  747 GAUCACAGACACGGAAAGGU  748 UUGGCCUACUUACUUUGGCU  749 CUUGGCCUACUUACUUUGGC  750 ACUUGGCCUACUUACUUUGG  751 GAGGAACUUGGCCUACUUAC  752 CGAGGAACUUGGCCUACUUA  753 CCGAGGAACUUGGCCUACUU  754 ACCGAGGAACUUGGCCUACU  755 AACCGAGGAACUUGGCCUAC  756 GAACCGAGGAACUUGGCCUA  757 GGAACCGAGGAACUUGGCCU  758 AGGAACCGAGGAACUUGGCC  759 UAGGAACCGAGGAACUUGGC  760 AUAGGAACCGAGGAACUUGG  761 UAUAGGAACCGAGGAACUUG  762 AUCACAAGUUGCCACUGUUG  763 CAUCACAAGUUGCCACUGUU  764 AUCAUCACAAGUUGCCACUG  765 CAUCAUCACAAGUUGCCACU  766 CUGCUCCAUCAUCACAAGUU  767 UCUGCUCCAUCAUCACAAGU  768 CCCUCUGCUCCAUCAUCACA  769 UCAGCCCUCUGCUCCAUCAU  770 UGACUUCAGCCCUCUGCUCC  771 GUGACUUCAGCCCUCUGCUC  772 UGUGACUUCAGCCCUCUGCU  773 GUGUGACUUCAGCCCUCUGC  774 UGUGUGACUUCAGCCCUCUG  775 GCCCACUCCGCUGCUUUUAG  776 GGCCCACUCCGCUGCUUUUA  777 AGGCCCACUCCGCUGCUUUU  778 UAGGCCCACUCCGCUGCUUU  779 UUAGGCCCACUCCGCUGCUU  780 AUUAGGCCCACUCCGCUGCU  781 UCAUUAGGCCCACUCCGCUG  782 CUCAUUAGGCCCACUCCGCU  783 AGCUCAUUAGGCCCACUCCG  784 CUCCCAUAGAAAAGCUCACU  785 GCUCCCAUAGAAAAGCUCAC  786 UGCUCCCAUAGAAAAGCUCA  787 CUGCUCCCAUAGAAAAGCUC  788 CCUGCUCCCAUAGAAAAGCU  789 UCCCUAUCUCCUGCUAACCC  790 CCUCGAACUCUCCCUAUCUC  791 CCCUCGAACUCUCCCUAUCU  792 UCCCUCGAACUCUCCCUAUC  793 GUCCCUCGAACUCUCCCUAU  794 CUUUCCAUACUAGCUUCUGA  795 CCUUUCCAUACUAGCUUCUG  796 ACCUUUCCAUACUAGCUUCU  797 CACACAAAUCACCUUUCCAU  798 GUCACACAAAUCACCUUUCC  799 UGUCACACAAAUCACCUUUC  800 UUUGACAGGCAGGAAGUGGC  801 GGUUUGACAGGCAGGAAGUG  802 AGGUUUGACAGGCAGGAAGU  803 AAGGUUUGACAGGCAGGAAG  804 AACUUCCCAAGGUUUGACAG  805 CAACUUCCCAAGGUUUGACA  806 GAACAACUUCCCAAGGUUUG  807 UGAACAACUUCCCAAGGUUU  808 GUAGGUUGAACAACUUCCCA  809 GGUAGGUUGAACAACUUCCC  810 UGGUAGGUUGAACAACUUCC  811 GGUUUUGGUAGGUUGAACAA  812 UGAGGUUUUGGUAGGUUGAA  813 CUGAGGUUUUGGUAGGUUGA  814 CCUACAUUAUCCUCUUACUC  815 GGACUUUACCUACAUUAUCC  816 GUAUGAGGACUUUACCUACA  817 GCCAGGUAUGAGGACUUUAC  818 UGCCAGGUAUGAGGACUUUA  819 GUGCCAGGUAUGAGGACUUU  820 CUGUGCCAGGUAUGAGGACU  821 UCUGUGCCAGGUAUGAGGAC  822 CCUCAAGAGUUCUCCAGAAG  823 CCCUCAAGAGUUCUCCAGAA  824 ACCCUCAAGAGUUCUCCAGA  825 ACACCCUCAAGAGUUCUCCA  826 CACACCCUCAAGAGUUCUCC  827 CCACACCCUCAAGAGUUCUC  828 CCCACACCCUCAAGAGUUCU  829 UUCCCACACCCUCAAGAGUU  830 CAAUGCUGCACCUCACUUCC  831 UACAAUGCUGCACCUCACUU  832 CUACAAUGCUGCACCUCACU  833 UCUACAAUGCUGCACCUCAC  834 AUCUACAAUGCUGCACCUCA  835 UAUCUACAAUGCUGCACCUC  836 CUUAUCUACAAUGCUGCACC  837 GUCUUAUCUACAAUGCUGCA  838 UGUCUUAUCUACAAUGCUGC  839 CUGUCUUAUCUACAAUGCUG  840 CACCCUUCUGUCUUAUCUAC  841 UCCACCCUUCUGUCUUAUCU  842 GUCCACCCUUCUGUCUUAUC  843 AGUCCACCCUUCUGUCUUAU  844 AAGUCCACCCUUCUGUCUUA  845 GAAAGCAAGCCAGGUUCUCA  846 GGAAAGCAAGCCAGGUUCUC  847 GGAAUUGGAAAGCAAGCCAG  848 ACCAUGUCAUUGGCAUCUCC  849 UACCAUGUCAUUGGCAUCUC  850 CCUACCAUGUCAUUGGCAUC  851 UCCUACCAUGUCAUUGGCAU  852 CUCCUACCAUGUCAUUGGCA  853 GCUCCUACCAUGUCAUUGGC  854 UGCUCCUACCAUGUCAUUGG  855 UCUUUGCUCCUACCAUGUCA  856 CCUCUUUGCUCCUACCAUGU  857 UUCCUCUUUGCUCCUACCAU  858 UCUCCGUGUUCUUCAGUUUU  859 CUCUCCGUGUUCUUCAGUUU  860 AGCUCUCCGUGUUCUUCAGU  861 UGCAGCUCUCCGUGUUCUUC  862 GGUUGCAGCUCUCCGUGUUC  863 AGGUUGCAGCUCUCCGUGUU  864 AAAGGUUGCAGCUCUCCGUG  865 UAAAGGUUGCAGCUCUCCGU  866 CUAAAGGUUGCAGCUCUCCG  867 CCUAAAGGUUGCAGCUCUCC  868 UCCUAAAGGUUGCAGCUCUC  869 CUCCUAAAGGUUGCAGCUCU  870 CCUCCUAAAGGUUGCAGCUC  871 GCACUUUGAUACCUCCUAAA  872 GGCACUUUGAUACCUCCUAA  873 GAUGUCCCACUUUGACUUUC  874 UCGAUGUCCCACUUUGACUU  875 GUCGAUGUCCCACUUUGACU  876 GGUCGAUGUCCCACUUUGAC  877 UGGUCGAUGUCCCACUUUGA  878 UUGGUCGAUGUCCCACUUUG  879 AUUGGUCGAUGUCCCACUUU  880 CAUUGGUCGAUGUCCCACUU  881 AACAUCCAUCAGUUGGCUCU  882 CUGCCCAACAUCCAUCAGUU  883 AGCUGCCCAACAUCCAUCAG  884 UAGCUGCCCAACAUCCAUCA  885 UUAGCUGCCCAACAUCCAUC  886 UUUAGCUGCCCAACAUCCAU  887 CUUUAGCUGCCCAACAUCCA  888 CCUCUUUAGCUGCCCAACAU  889 CCCUCUUUAGCUGCCCAACA  890 UCCCUCUUUAGCUGCCCAAC  891 UUCCCUCUUUAGCUGCCCAA  892 CCUUCCCUCUUUAGCUGCCC  893 CCCUUCCCUCUUUAGCUGCC  894 GCAGGUCUUAUCCCAUGCCC  895 GGGCAGGUCUUAUCCCAUGC  896 AGGGCAGGUCUUAUCCCAUG  897 AAGGGCAGGUCUUAUCCCAU  898 GAAGGGCAGGUCUUAUCCCA  899 AGAAGGGCAGGUCUUAUCCC  900 CCAAUGGCAAGAAGCAAGAA  901 CCCAAUGGCAAGAAGCAAGA  902 GCCCAAUGGCAAGAAGCAAG  903 UCCAAUGCCUGCCCAAUGGC  904 CUCCAAUGCCUGCCCAAUGG  905 UCUCCAAUGCCUGCCCAAUG  906 GGUCUCCAAUGCCUGCCCAA  907 UAGGGUCUCCAAUGCCUGCC  908 GUAGGGUCUCCAAUGCCUGC  909 AGUAGGGUCUCCAAUGCCUG  910 CAGUAGGGUCUCCAAUGCCU  911 GCAGUAGGGUCUCCAAUGCC  912 AGCAGUAGGGUCUCCAAUGC  913 CAGCAGUAGGGUCUCCAAUG  914 UCAGCAGUAGGGUCUCCAAU  915 AUUCAGCAGUAGGGUCUCCA  916 CAUUCAGCAGUAGGGUCUCC  917 CCAUUCAGCAGUAGGGUCUC  918 UCCAUUCAGCAGUAGGGUCU  919 ACUCCAUUCAGCAGUAGGGU  920 CACUCCAUUCAGCAGUAGGG  921 GCACUCCAUUCAGCAGUAGG  922 AGCACUCCAUUCAGCAGUAG  923 UAGCACUCCAUUCAGCAGUA  924 GUUAGCACUCCAUUCAGCAG  925 GGUUAGCACUCCAUUCAGCA  926 GGGUUAGCACUCCAUUCAGC  927 CAGGGUUAGCACUCCAUUCA  928 CCAGGGUUAGCACUCCAUUC  929 ACCAGGGUUAGCACUCCAUU  930 CACCAGGGUUAGCACUCCAU  931 GCACCAGGGUUAGCACUCCA  932 AGCACCAGGGUUAGCACUCC  933 UAGCACCAGGGUUAGCACUC  934 CUAGCACCAGGGUUAGCACU  935 UCUAGCACCAGGGUUAGCAC  936 CUCUAGCACCAGGGUUAGCA  937 CCUCUAGCACCAGGGUUAGC  938 UCCUCUAGCACCAGGGUUAG  939 CUCCUCUAGCACCAGGGUUA  940 CCUCCUCUAGCACCAGGGUU  941 UCCUCCUCUAGCACCAGGGU  942 GUUCCAUCCUCCUCUAGCAC  943 AAGUCCUCACUGUCCACUGC  944 GAAGUCCUCACUGUCCACUG  945 AGAAGUCCUCACUGUCCACU  946 AAGAAGUCCUCACUGUCCAC  947 GAAGAAGUCCUCACUGUCCA  948 GGAAGAAGUCCUCACUGUCC  949 UGGAAGAAGUCCUCACUGUC  950 CUGGAAGAAGUCCUCACUGU  951 AGCUGGAAGAAGUCCUCACU  952 ACUGCAACACCAUCAGGCAC  953 GACUGCAACACCAUCAGGCA  954 AGACUGCAACACCAUCAGGC  955 CAGACUGCAACACCAUCAGG  956 CCAGACUGCAACACCAUCAG  957 GACCAGACUGCAACACCAUC  958 CUCUGACCAGACUGCAACAC  959 AGCUCUGACCAGACUGCAAC  960 CCAGCUCUGACCAGACUGCA  961 UGUAGGGCUCCAGCUCUGAC  962 CUUGUAGGGCUCCAGCUCUG  963 CCUUGUAGGGCUCCAGCUCU  964 ACAGGCAUUGGAAGCAGCCC  965 GACAGGCAUUGGAAGCAGCC  966 AAGGACAGGCAUUGGAAGCA  967 AAAGGACAGGCAUUGGAAGC  968 UAAAGGACAGGCAUUGGAAG  969 CUAAAGGACAGGCAUUGGAA  970 GCUCUAAAGGACAGGCAUUG  971 AGCUCUAAAGGACAGGCAUU  972 AAGCUCUAAAGGACAGGCAU  973 AAAGCUCUAAAGGACAGGCA  974 GAAAGCUCUAAAGGACAGGC  975 CGGGAAAGCUCUAAAGGACA  976 CCGGGAAAGCUCUAAAGGAC  977 AGGGUUAAGCUAGAGAGGAA  978 UCAGGGUUAAGCUAGAGAGG  979 GAUCAGGGUUAAGCUAGAGA  980 GGAUCAGGGUUAAGCUAGAG  981 AGGAUCAGGGUUAAGCUAGA  982 CCCAGGAUCAGGGUUAAGCU  983 CAACUCCUCCUGCACCUGGU  984 ACAACUCCUCCUGCACCUGG  985 GACAAUUCCACAACUCCUCC  986 UGACAAUUCCACAACUCCUC  987 UUGACAAUUCCACAACUCCU  988 CUUGACAAUUCCACAACUCC  989 UCCUUGACAAUUCCACAACU  990 AUCCUUGACAAUUCCACAAC  991 CAUCCUUGACAAUUCCACAA  992 ACAUCCUUGACAAUUCCACA  993 GACAUCCUUGACAAUUCCAC  994 UGACAUCCUUGACAAUUCCA  995 UGUGUGACAUCCUUGACAAU  996 ACUGUGUGACAUCCUUGACA  997 ACUUUCUGUCCACUGUGUGA  998 CCUCGCUUGGACUUUCUGUC  999 CCCUCGCUUGGACUUUCUGU 1000 UCCCUCGCUUGGACUUUCUG 1001 CUCCCUCGCUUGGACUUUCU 1002 CCUCCCUCGCUUGGACUUUC 1003 CCCUCCCUCGCUUGGACUUU 1004 UCCAUCAGCACUGGGUCAGA 1005 ACCACUAAUCUCCAUCAGCA 1006 CACCACUAAUCUCCAUCAGC 1007 CCACCACUAAUCUCCAUCAG 1008 CCCACCACUAAUCUCCAUCA 1009 ACCAGACACCCACCACUAAU 1010 UACCAGACACCCACCACUAA 1011 CUCAUACCAGACACCCACCA 1012 CCUCAUACCAGACACCCACC 1013 UCCUCAUACCAGACACCCAC 1014 AUCCUCAUACCAGACACCCA 1015 GAUCCUCAUACCAGACACCC 1016 AGAUCCUCAUACCAGACACC 1017 UAGAUCCUCAUACCAGACAC 1018 GUAGAUCCUCAUACCAGACA 1019 AGUAGAUCCUCAUACCAGAC 1020 CAGUAGAUCCUCAUACCAGA 1021 UGCAGUAGAUCCUCAUACCA 1022 GUGCAGUAGAUCCUCAUACC 1023 AGUGCAGUAGAUCCUCAUAC 1024 ACUCUGUAGGACACCCUUGU 1025 CACUCUGUAGGACACCCUUG 1026 CCACUCUGUAGGACACCCUU 1027 UCCACUCUGUAGGACACCCU 1028 CUCCACUCUGUAGGACACCC 1029 ACUCCACUCUGUAGGACACC 1030 CACUCCACUCUGUAGGACAC 1031 AGCACUCCACUCUGUAGGAC 1032 UAUGACAGCACUCCACUCUG 1033 AUAUGACAGCACUCCACUCU 1034 UUGCUGUGCUUGGGCCUCUC 1035 ACGUCAAAGGUGAAUCGGGC 1036 CACGUCAAAGGUGAAUCGGG 1037 ACACGUCAAAGGUGAAUCGG 1038 UACACGUCAAAGGUGAAUCG 1039 GUACACGUCAAAGGUGAAUC 1040 GGCUGCCAAAGAGGUCUCGA 1041 UCAGGCUGCCAAAGAGGUCU 1042 CAUUCAGGCUGCCAAAGAGG 1043 GACAUUCAGGCUGCCAAAGA 1044 UGACAUUCAGGCUGCCAAAG 1045 CUUUGACAUUCAGGCUGCCA 1046 GCUUUGACAUUCAGGCUGCC 1047 CCGUAGAAUGUGGCUUUGAC 1048 GCCCGUAGAAUGUGGCUUUG 1049 UAGAGCCCGUAGAAUGUGGC 1050 GUAGAGCCCGUAGAAUGUGG 1051 AGUAGAGCCCGUAGAAUGUG 1052 AGAGUAGAGCCCGUAGAAUG 1053 UAGAGUAGAGCCCGUAGAAU 1054 AUAGAGUAGAGCCCGUAGAA 1055 CAUAGAGUAGAGCCCGUAGA 1056 UCAUAGAGUAGAGCCCGUAG 1057 CUCAUAGAGUAGAGCCCGUA 1058 GAAAGUCACAACUCAUAGAG 1059 CCUUGAAAGUCACAACUCAU 1060 AAGUCCUUGAAAGUCACAAC 1061 CCAAGUCCUUGAAAGUCACA 1062 UUCUUUGGGCCAAGUCCUUG 1063 UUUCUUUGGGCCAAGUCCUU 1064 UUGAUUUCUGACCUGAGUAC 1065 GUUGAUUUCUGACCUGAGUA 1066 GGGACUAUCCAACUGUAGGG 1067 GCAAGAGGACGAAUUAUGGG 1068 UGCAAGAGGACGAAUUAUGG 1069 GUGCAAGAGGACGAAUUAUG 1070 GGUGCAAGAGGACGAAUUAU 1071 GGGUGCAAGAGGACGAAUUA 1072 UGGGUGCAAGAGGACGAAUU 1073 GUGGGUGCAAGAGGACGAAU 1074 GGUGGGUGCAAGAGGACGAA 1075 UAGGUGGGUGCAAGAGGACG 1076 GUAGGUGGGUGCAAGAGGAC 1077 GGUAGGUGGGUGCAAGAGGA 1078 CCACAAGCAAGAGCUAACUA 1079 ACUUUCCACAAGCAAGAGCU 1080 GACUUUCCACAAGCAAGAGC 1081 GGACUUUCCACAAGCAAGAG 1082 AGGACUUUCCACAAGCAAGA 1083 GAGGACUUUCCACAAGCAAG 1084 UGAGGACUUUCCACAAGCAA 1085 AUGAGGACUUUCCACAAGCA 1086 GAUGAGGACUUUCCACAAGC 1087 AGAUGAGGACUUUCCACAAG 1088 GAGAUGAGGACUUUCCACAA 1089 GGAGAUGAGGACUUUCCACA 1090 UGGGAGAUGAGGACUUUCCA 1091 GCUGGGAGAUGAGGACUUUC 1092 UCAAGCUGGGAGAUGAGGAC 1093 AAGCCAUCAAGCUGGGAGAU 1094 GAAGCCAUCAAGCUGGGAGA 1095 GGAGGAAGCCAUCAAGCUGG 1096 GGGAGGAAGCCAUCAAGCUG 1097 AACUUGGGAGGAAGCCAUCA 1098 AAACUUGGGAGGAAGCCAUC 1099 CAGCAGUGUGGAGGUCCAAC 1100 GCAGCAGUGUGGAGGUCCAA 1101 UGCAGCAGUGUGGAGGUCCA 1102 UUGCAGCAGUGUGGAGGUCC 1103 GGUGGAGGAAAUUCCCAGCA 1104 ACGAAGGGUGGAGGAAAUUC 1105 GACGAAGGGUGGAGGAAAUU 1106 AUGACGAAGGGUGGAGGAAA 1107 CAUGACGAAGGGUGGAGGAA 1108 GCAUGACGAAGGGUGGAGGA 1109 UGCAUGACGAAGGGUGGAGG 1110 CUGCAUGACGAAGGGUGGAG 1111 ACUGCAUGACGAAGGGUGGA 1112 CACUGCAUGACGAAGGGUGG 1113 CCACUGCAUGACGAAGGGUG 1114 UCCACUGCAUGACGAAGGGU 1115 CUCCACUGCAUGACGAAGGG 1116 CCUCCACUGCAUGACGAAGG 1117 CCCUCCACUGCAUGACGAAG 1118 CUUAGUAGGAAUGGAGGCGG 1119 CCUUAGUAGGAAUGGAGGCG 1120 CCCUUAGUAGGAAUGGAGGC 1121 UCGGUUGGAAUGAUUCUGGG 1122 GUCGGUUGGAAUGAUUCUGG 1123 GGUCGGUUGGAAUGAUUCUG 1124 GGGUCGGUUGGAAUGAUUCU 1125 UGGGUCGGUUGGAAUGAUUC 1126 GUGGGUCGGUUGGAAUGAUU 1127 AGUGGGUCGGUUGGAAUGAU 1128 CAGUGGGUCGGUUGGAAUGA 1129 GCAGUGGGUCGGUUGGAAUG 1130 UGCAGUGGGUCGGUUGGAAU 1131 UUGCAGUGGGUCGGUUGGAA 1132 UUUGCAGUGGGUCGGUUGGA 1133 CUUUGCAGUGGGUCGGUUGG 1134 UCUUUGCAGUGGGUCGGUUG 1135 UAGUCUUUGCAGUGGGUCGG 1136 AUAGUCUUUGCAGUGGGUCG 1137 CUGUCAUAGUCUUUGCAGUG 1138 UGCUGUCAUAGUCUUUGCAG 1139 UCUAGCCUGUACUGUCUGCA 1140 AUCUAGCCUGUACUGUCUGC 1141 UAUCUAGCCUGUACUGUCUG 1142 UUAUCUAGCCUGUACUGUCU 1143 GUUAUCUAGCCUGUACUGUC 1144 GGUUAUCUAGCCUGUACUGU 1145 GGGUUAUCUAGCCUGUACUG 1146 UGGGUUAUCUAGCCUGUACU 1147 GUGGGUUAUCUAGCCUGUAC 1148 GGUGGGUUAUCUAGCCUGUA 1149 GGGUGGGUUAUCUAGCCUGU 1150 UGGGUGGGUUAUCUAGCCUG 1151 UUGGGUGGGUUAUCUAGCCU 1152 AUUGGGUGGGUUAUCUAGCC 1153 AAUUGGGUGGGUUAUCUAGC 1154 AAAUUGGGUGGGUUAUCUAG 1155 GGAAAUUGGGUGGGUUAUCU 1156 GGGAAAUUGGGUGGGUUAUC 1157 GAAAGGUUCUGUCACGAGGG 1158 GCUGAAAGGUUCUGUCACGA 1159 UGCUGAAAGGUUCUGUCACG 1160 GGCGUUAUGCUGAAAGGUUC 1161 AGGCGUUAUGCUGAAAGGUU 1162 GAGGCGUUAUGCUGAAAGGU 1163 UGAGGCGUUAUGCUGAAAGG 1164 GUGAGGCGUUAUGCUGAAAG 1165 AUGUGAGGCGUUAUGCUGAA 1166 GAUGUGAGGCGUUAUGCUGA 1167 GGAUGUGAGGCGUUAUGCUG 1168 GGGAUGUGAGGCGUUAUGCU 1169 CUUGGGAUGUGAGGCGUUAU 1170 AGACUUGGGAUGUGAGGCGU 1171 UAGACUUGGGAUGUGAGGCG 1172 AUAGACUUGGGAUGUGAGGC 1173 UAUAGACUUGGGAUGUGAGG 1174 GGGUAUAGACUUGGGAUGUG 1175 AGGGUAUAGACUUGGGAUGU 1176 AAGGUGGCUAGGAAAGAACA 1177 AAAGGUGGCUAGGAAAGAAC 1178 GAAAGGUGGCUAGGAAAGAA 1179 ACAUCUUGAUCUUGGCCUUU 1180 GGCUGGGAUCAAGAUGCCUG 1181 GUCAGGCUGGGAUCAAGAUG 1182 AGUCAGGCUGGGAUCAAGAU 1183 CAGUCAGGCUGGGAUCAAGA 1184 AGCAGUCAGGCUGGGAUCAA 1185 GAUGUAGCAGCAGUCAGGCU 1186 GGAUUAGAUGUAGCAGCAGU 1187 GGGAUUAGAUGUAGCAGCAG 1188 GACAGGAGGCAUUGGUAGGG 1189 UUAGGGACAGGAGGCAUUGG 1190 UUUAGGGACAGGAGGCAUUG 1191 GAGUUUAGGGACAGGAGGCA 1192 GGAGUUUAGGGACAGGAGGC 1193 GCUGUCAUCAGUAUGCUGGG 1194 GGCUGUCAUCAGUAUGCUGG 1195 GGGCUGUCAUCAGUAUGCUG 1196 AGGGCUGUCAUCAGUAUGCU 1197 AGAGAGGGCUGUCAUCAGUA 1198 CAGAGAGGGCUGUCAUCAGU 1199 UCAGAGAGGGCUGUCAUCAG 1200 GUCAGAGAGGGCUGUCAUCA 1201 GGUAAAGUCAGAGAGGGCUG 1202 GGGAAGGGUAUGAAGACAGA 1203

In some embodiments, the antisense nucleic acid molecules targeted to Transcript B comprise or consist of the nucleotide sequences shown in Table 3.

TABLE 3 SEQ ID Sequence NO: UUGCCUUCGGCUUGCUCUGG 1204 CUUGCCUUCGGCUUGCUCUG 1205 GCUUGCCUUCGGCUUGCUCU 1206 UGCUUGCCUUCGGCUUGCUC 1207 GUGCUUGCCUUCGGCUUGCU 1208 UCGUGCUUGCCUUCGGCUUG 1209 AUCGUGCUUGCCUUCGGCUU 1210 CAUCGUGCUUGCCUUCGGCU 1211 AGCGCCAUCGUGCUUGCCUU 1212 UGGUGAGCGCCAUCGUGCUU 1213 CUGAUGCUCGGCUGCUACAG 1214 GCUGAUGCUCGGCUGCUACA 1215 UUUCGGGCUGAUGCUCGGCU 1216 UCCUUUCGGGCUGAUGCUCG 1217 UUCCUUUCGGGCUGAUGCUC 1218 CUUCCUUUCGGGCUGAUGCU 1219 GCUUCCUUUCGGGCUGAUGC 1220 UGCUUCCUUUCGGGCUGAUG 1221 GUGCUUCCUUUCGGGCUGAU 1222 CGUGCUUCCUUUCGGGCUGA 1223 UCGUGCUUCCUUUCGGGCUG 1224 UUCGUGCUUCCUUUCGGGCU 1225 UUUCGUGCUUCCUUUCGGGC 1226 CUUUCGUGCUUCCUUUCGGG 1227 GCUUUCGUGCUUCCUUUCGG 1228 AUGUACGCCAGCGUGCUGCU 1229 UCAGCAUGUACGCCAGCGUG 1230 AGGCGGUGUACUACGUGUGC 1231 AAGGCGGUGUACUACGUGUG 1232 CAAGGCGGUGUACUACGUGU 1233 GCAAGGCGGUGUACUACGUG 1234 UGCAAGGCGGUGUACUACGU 1235 CUGCAAGGCGGUGUACUACG 1236 GCUGCAAGGCGGUGUACUAC 1237 GGCUGCAAGGCGGUGUACUA 1238 GCUCUUUGUGGCCUUCCUGA 1239 CGCUCUUUGUGGCCUUCCUG 1240 CUUCGUGGUGUGGAGCUUGG 1241 GGCUUCGUGGUGUGGAGCUU 1242 CAACGGCUUCGUGGUGUGGA 1243 UGGCAACGGCUUCGUGGUGU 1244 UGAGCUGGAAGACUUCGCGG 1245 CUGAGCUGGAAGACUUCGCG 1246 GCUGAGCUGGAAGACUUCGC 1247 ACACUGCUGAGCUGGAAGAC 1248 CGAGACACUGCUGAGCUGGA 1249 ACGAGACACUGCUGAGCUGG 1250 AACGAGACACUGCUGAGCUG 1251 GAACGAGACACUGCUGAGCU 1252 GGAACGAGACACUGCUGAGC 1253 GGGAACGAGACACUGCUGAG 1254 AGGGAACGAGACACUGCUGA 1255 CAGGGAACGAGACACUGCUG 1256 CCAGGGAACGAGACACUGCU 1257 AAGGAUGUCGGUCUGCUACC 1258 GAAGGAUGUCGGUCUGCUAC 1259 AGAAGGAUGUCGGUCUGCUA 1260 UAGGCCCAGAAGGAUGUCGG 1261 GUAGGCCCAGAAGGAUGUCG 1262 UGUAGGCCCAGAAGGAUGUC 1263 CUGUAGGCCCAGAAGGAUGU 1264 CCUGUAGGCCCAGAAGGAUG 1265 ACCUGUAGGCCCAGAAGGAU 1266 CUUCUCAUCGGGCAUCACAG 1267 CCUUCUCAUCGGGCAUCACA 1268 ACCUUCUCAUCGGGCAUCAC 1269 CACCUUCUCAUCGGGCAUCA 1270 GCACCUUCUCAUCGGGCAUC 1271 GGCACCUUCUCAUCGGGCAU 1272 UGGCACCUUCUCAUCGGGCA 1273 AUGGCACCUUCUCAUCGGGC 1274 CAUGGCACCUUCUCAUCGGG 1275 GCAUGGCACCUUCUCAUCGG 1276 GGCAUGGCACCUUCUCAUCG 1277 GAGGCAUGGCACCUUCUCAU 1278 GGAGGCAUGGCACCUUCUCA 1279 GACUCCCAGGCAGAAAAGAG 1280 GGACUCCCAGGCAGAAAAGA 1281 AGGACUCCCAGGCAGAAAAG 1282 UCAGGACUCCCAGGCAGAAA 1283 GAAGUCAGGACUCCCAGGCA 1284 GUGGAAGUCAGGACUCCCAG 1285 UCGUGGAAGUCAGGACUCCC 1286 CUCGUGGAAGUCAGGACUCC 1287 CCUCGUGGAAGUCAGGACUC 1288 UGGGUCCUCGUGGAAGUCAG 1289 CUGGGUCCUCGUGGAAGUCA 1290 UCUGGGUCCUCGUGGAAGUC 1291 GUCUGGGUCCUCGUGGAAGU 1292 AAGAAGGAGUUGUGUUUGAG 1293 CCAAGAAGGAGUUGUGUUUG 1294 GUUCCAAGAAGGAGUUGUGU 1295 GGUUCCAAGAAGGAGUUGUG 1296 CAGGUCAACUGACUGGGAGC 1297 UGCCUGUUUACCACUGAGCU 1298 AUGCCUGUUUACCACUGAGC 1299 UAUGCCUGUUUACCACUGAG 1300 UUAUGCCUGUUUACCACUGA 1301 UUUAUGCCUGUUUACCACUG 1302 CUUUAUGCCUGUUUACCACU 1303 ACUUUAUGCCUGUUUACCAC 1304 UAGAGAUAGUGACAGCCUGG 1305 GUAGAGAUAGUGACAGCCUG 1306 UGGUGGUAGAGAUAGUGACA 1307 GUGGUGGUAGAGAUAGUGAC 1308 UAGAGGAGUGGUGGUAGAGA 1309 ACUAGAGGAGUGGUGGUAGA 1310 AGACUAGAGGAGUGGUGGUA 1311 CAGACUAGAGGAGUGGUGGU 1312 CCAGACUAGAGGAGUGGUGG 1313 GCCAGACUAGAGGAGUGGUG 1314 GGCCAGACUAGAGGAGUGGU 1315 GCCCAGAUGUGCUAGAAUGG 1316 UGCCCAGAUGUGCUAGAAUG 1317 UUGCCCAGAUGUGCUAGAAU 1318 UUUGCCCAGAUGUGCUAGAA 1319 UUUUGCCCAGAUGUGCUAGA 1320 CCAGUUUUGCCCAGAUGUGC 1321 AUCCAGUUUUGCCCAGAUGU 1322 CCAUCCAGUUUUGCCCAGAU 1323 CACCAUCCAGUUUUGCCCAG 1324 CCACCAUCCAGUUUUGCCCA 1325 CCCACCAUCCAGUUUUGCCC 1326 UUGCUCCCAGCUUGGUAAGU 1327 GCUUGCUCCCAGCUUGGUAA 1328 AUCCUGCUUGCUCCCAGCUU 1329 AAUCCUGCUUGCUCCCAGCU 1330 CAAUCCUGCUUGCUCCCAGC 1331 CCAAUCCUGCUUGCUCCCAG 1332 AACCUUUCAGCUUCUCCAGG 1333 UAACCUUUCAGCUUCUCCAG 1334 UUAACCUUUCAGCUUCUCCA 1335 ACUGCUGCUUAACCUUUCAG 1336 UACUGCUGCUUAACCUUUCA 1337 CUACUGCUGCUUAACCUUUC 1338 CCUACUGCUGCUUAACCUUU 1339 GCCUACUGCUGCUUAACCUU 1340 CAGGACAGGAGUAGGCACCU 1341 ACAGGACAGGAGUAGGCACC 1342 GCACAGGACAGGAGUAGGCA 1343 AUAGGCACAGGACAGGAGUA 1344 GAUAGGCACAGGACAGGAGU 1345 UGAUAGGCACAGGACAGGAG 1346 ACCCUCUGCAAAUGUGAUAG 1347 CUUACCCUCUGCAAAUGUGA 1348 GUCUUACCCUCUGCAAAUGU 1349 UGUCUUACCCUCUGCAAAUG 1350 UUGUCUUACCCUCUGCAAAU 1351 CUUGUCUUACCCUCUGCAAA 1352 UCUUGUCUUACCCUCUGCAA 1353 CAUUCUUGUCUUACCCUCUG 1354 CCCAUUCUUGUCUUACCCUC 1355 GAGCCUCAUCUUGUCCCUCC 1356 UGAGCCUCAUCUUGUCCCUC 1357 UGCGUUGGUGAUGGGAAGGA 1358 GUGCGUUGGUGAUGGGAAGG 1359 GGUGCGUUGGUGAUGGGAAG 1360 GGGUGCGUUGGUGAUGGGAA 1361 UGGGUGCGUUGGUGAUGGGA 1362 UCUCACAUGCCUGGACGCCU 1363 CAAGGCAGGCUCUCACAUGC 1364 UGCUGUUUCCUGGCAAGGCA 1365 UUGUGCUGUUUCCUGGCAAG 1366 CUUGUGCUGUUUCCUGGCAA 1367 ACCACCAGGGAAUCUUACUG 1368 UCCACCACCAGGGAAUCUUA 1369 AUUUCCUUCCACCACCAGGG 1370 UAUUUCCUUCCACCACCAGG 1371 CCUAUUUCCUUCCACCACCA 1372 AGUCCUCCUAUUUCCUUCCA 1373 AGAGUCCUCCUAUUUCCUUC 1374 AGCAGAGUCCUCCUAUUUCC 1375 CAGCAGAGUCCUCCUAUUUC 1376 AUUCAGCAGAGUCCUCCUAU 1377 ACCAGGAUUCAGCAGAGUCC 1378 GACCAGGAUUCAGCAGAGUC 1379 GGACCAGGAUUCAGCAGAGU 1380 CAGGACCAGGAUUCAGCAGA 1381 CAGAAGCAGGACCAGGAUUC 1382 ACAGAAGCAGGACCAGGAUU 1383 AACAGAAGCAGGACCAGGAU 1384 AGAACAGAAGCAGGACCAGG 1385 GGGAGGGAUGAGAACAGAAG 1386 CAGGCAACAUACACACUGCA 1387 CCAGGCAACAUACACACUGC 1388 ACCAGGCAACAUACACACUG 1389 AGACCAGGCAACAUACACAC 1390 GAGAGACCAGGCAACAUACA 1391 CCAGAGAGACCAGGCAACAU 1392 UUGUUUGGGUCACCUCUGCA 1393 GUUGUUUGGGUCACCUCUGC 1394 AGUUGUUUGGGUCACCUCUG 1395 UGAGUUGUUUGGGUCACCUC 1396 CUGAGUUGUUUGGGUCACCU 1397 GACUGAGUUGUUUGGGUCAC 1398 AAACAGGCAAGGAUAAGGCA 1399 ACAUGGAAAAGCUGUCAUUG 1400 CCUUACAUGGAAAAGCUGUC 1401 GCCUUACAUGGAAAAGCUGU 1402 CUCCUGGAACCUAGCACCAU 1403 CCUCCUGGAACCUAGCACCA 1404 UCCUCCUGGAACCUAGCACC 1405 AACCAUUAUGCCUCCAUGCA 1406 UAACCAUUAUGCCUCCAUGC 1407 CUAACCAUUAUGCCUCCAUG 1408 CCUAACCAUUAUGCCUCCAU 1409 CCCUAACCAUUAUGCCUCCA 1410 ACUCCCUAACCAUUAUGCCU 1411 GACUCCCUAACCAUUAUGCC 1412 UGACUCCCUAACCAUUAUGC 1413 AUGACUCCCUAACCAUUAUG 1414 CAUGACUCCCUAACCAUUAU 1415 GGGCCUCUUCAUGGUUGUGU 1416 UGGUGCAGCCUGGUAAUGGG 1417 CUGGUGCAGCCUGGUAAUGG 1418 CCUGGUGCAGCCUGGUAAUG 1419 AUCCUGGUGCAGCCUGGUAA 1420 UAUCCUGGUGCAGCCUGGUA 1421 GUAUCCUGGUGCAGCCUGGU 1422 UGUAUCCUGGUGCAGCCUGG 1423 UCUUGUAUCCUGGUGCAGCC 1424 GUCUUGUAUCCUGGUGCAGC 1425 UGUCUUGUAUCCUGGUGCAG 1426 UUGUCUUGUAUCCUGGUGCA 1427 CUUGUCUUGUAUCCUGGUGC 1428 UCUUGUCUUGUAUCCUGGUG 1429 UUCUUGUCUUGUAUCCUGGU 1430 UUUCUUGUCUUGUAUCCUGG 1431 CCUUUCUUGUCUUGUAUCCU 1432 ACUCAUCCUUUCCUUUCUUG 1433 CCUACUCAUCCUUUCCUUUC 1434 CCCUACUCAUCCUUUCCUUU 1435 UCCCUACUCAUCCUUUCCUU 1436 GCUUCUUAGUAUGUCCCUAC 1437 GCUGCUUCUUAGUAUGUCCC 1438 GGCUGCUUCUUAGUAUGUCC 1439 GGGCUGCUUCUUAGUAUGUC 1440 AGGGCUGCUUCUUAGUAUGU 1441 GAGAGGGCUGCUUCUUAGUA 1442 UCCAAGAGGAGAGGGCUGCU 1443 UUGACUUUUCCAAGAGGAGA 1444 AGCUCUAUCCAUCUGCCAGG 1445 GCUGUUACUUGAGCAGAGGC 1446 GGCUGUUACUUGAGCAGAGG 1447 UGGCUGUUACUUGAGCAGAG 1448 CUGGCUGUUACUUGAGCAGA 1449 UCUGGCUGUUACUUGAGCAG 1450 CCUCAAGUUCUGGCUGUUAC 1451 ACCUCAAGUUCUGGCUGUUA 1452 CAACCUCAAGUUCUGGCUGU 1453 GCAACCUCAAGUUCUGGCUG 1454 AGCAACCUCAAGUUCUGGCU 1455 CAAGCAACCUCAAGUUCUGG 1456 CCAAGCAACCUCAAGUUCUG 1457 CCCAAGCAACCUCAAGUUCU 1458 ACUAAGACAGUGCUCCUGGU 1459 CAAACUAAGACAGUGCUCCU 1460 AGCUCUGCUUUGGAAGAACC 1461 CCCUUAGCUCAAGCUCUGCU 1462 GCCCUUAGCUCAAGCUCUGC 1463 AAGCCCUUAGCUCAAGCUCU 1464 CAAGCCCUUAGCUCAAGCUC 1465 CCAAGCCCUUAGCUCAAGCU 1466 CCCAAGCCCUUAGCUCAAGC 1467 GUACCCAAGCCCUUAGCUCA 1468 UGUACCCAAGCCCUUAGCUC 1469 CUGUACCCAAGCCCUUAGCU 1470 CCUGUACCCAAGCCCUUAGC 1471 ACCUGUACCCAAGCCCUUAG 1472 UCACCUGUACCCAAGCCCUU 1473 AUCACCUGUACCCAAGCCCU 1474 GGAUCACCUGUACCCAAGCC 1475 CUCAAGAAUACAGGAUCACC 1476 CUUAGCUCAAGAAUACAGGA 1477 CCUUAGCUCAAGAAUACAGG 1478 GCCCUUAGCUCAAGAAUACA 1479 AGCCCUUAGCUCAAGAAUAC 1480 AAGCCCUUAGCUCAAGAAUA 1481 CAAGCCCUUAGCUCAAGAAU 1482 CCAAGCCCUUAGCUCAAGAA 1483 CCCAAGCCCUUAGCUCAAGA 1484 GUACCCAAGCCCUUAGCUCA 1485 UGUACCCAAGCCCUUAGCUC 1486 CUGUACCCAAGCCCUUAGCU 1487 CCUGUACCCAAGCCCUUAGC 1488 ACCUGUACCCAAGCCCUUAG 1489 UCACCUGUACCCAAGCCCUU 1490 AUCACCUGUACCCAAGCCCU 1491 GGAUCACCUGUACCCAAGCC 1492 UAACCUCCCAAAUACAGGAU 1493 UACCUUAUGCCCUCACUUCC 1494 UUACCUUAUGCCCUCACUUC 1495 UUUACCUUAUGCCCUCACUU 1496 UUUUACCUUAUGCCCUCACU 1497 UUGUUUUACCUUAUGCCCUC 1498 CUUGUUUUACCUUAUGCCCU 1499 UUAAUGGCUUUCCUCUCUCU 1500 ACUCUUAAUGGCUUUCCUCU 1501 UACUCUUAAUGGCUUUCCUC 1502 CAUACUCUUAAUGGCUUUCC 1503 GAAGGGACUUAACAUACUCU 1504 UGAAGGGACUUAACAUACUC 1505 ACUGAAGGGACUUAACAUAC 1506 CUACUGAAGGGACUUAACAU 1507 GCCUACUGAAGGGACUUAAC 1508 GGCCUACUGAAGGGACUUAA 1509 UUCUCAGAGGUUCCCAAGGC 1510 UUUUCUCAGAGGUUCCCAAG 1511 ACUUUUCUCAGAGGUUCCCA 1512 UACUUUUCUCAGAGGUUCCC 1513 GGGCAAUCUAUACUUUUCUC 1514 UGUCUUGGGCAAUCUAUACU 1515 CCAGUCUUUUGUCUUGGGCA 1516 GCCAGUCUUUUGUCUUGGGC 1517 UGCCAGUCUUUUGUCUUGGG 1518 CUGCCAGUCUUUUGUCUUGG 1519 UCACCCUGCCAGUCUUUUGU 1520 AUCACCCUGCCAGUCUUUUG 1521 GCCCACUCAUUAAGUACAUU 1522 CUGUAGCCCACUCAUUAAGU 1523 CGCUGUAGCCCACUCAUUAA 1524 ACGCUGUAGCCCACUCAUUA 1525 UACGCUGUAGCCCACUCAUU 1526 AUACGCUGUAGCCCACUCAU 1527 GAUACGCUGUAGCCCACUCA 1528 GGAUACGCUGUAGCCCACUC 1529 AGGAUACGCUGUAGCCCACU 1530 GAGGAUACGCUGUAGCCCAC 1531 UGAGGAUACGCUGUAGCCCA 1532 GUGAGGAUACGCUGUAGCCC 1533 UGUGAGGAUACGCUGUAGCC 1534 CUGUUGUGAGGAUACGCUGU 1535 UCUGUUGUGAGGAUACGCUG 1536 GUCUGUUGUGAGGAUACGCU 1537 UGUCUGUUGUGAGGAUACGC 1538 ACUGUCUGUUGUGAGGAUAC 1539 CACUGUCUGUUGUGAGGAUA 1540 CAACUCUCUCUCACUGUCUG 1541 AACAACUCUCUCUCACUGUC 1542 AGAACAACUCUCUCUCACUG 1543 GUAGAACAACUCUCUCUCAC 1544 GGUAGAACAACUCUCUCUCA 1545 CAGGUAGAACAACUCUCUCU 1546 CCAGGUAGAACAACUCUCUC 1547 ACCCAGGUAGAACAACUCUC 1548 UAUACCCAGGUAGAACAACU 1549 AUAUACCCAGGUAGAACAAC 1550 GGAUAUACCCAGGUAGAACA 1551 GUUUUGGAUAUACCCAGGUA 1552 CCUUGUUUUGGAUAUACCCA 1553 CCCUUGUUUUGGAUAUACCC 1554 CCUCGUAAACUCCAUACCCU 1555 CCCUCGUAAACUCCAUACCC 1556 ACCCUCGUAAACUCCAUACC 1557 AACCCUCGUAAACUCCAUAC 1558 GAACCCUCGUAAACUCCAUA 1559 UGAACCCUCGUAAACUCCAU 1560 UUGAACCCUCGUAAACUCCA 1561 CUUGAACCCUCGUAAACUCC 1562 CCUUGAACCCUCGUAAACUC 1563 ACCUUGAACCCUCGUAAACU 1564 UACCUUGAACCCUCGUAAAC 1565 AUACCUUGAACCCUCGUAAA 1566 AAUACCUUGAACCCUCGUAA 1567 AAAUACCUUGAACCCUCGUA 1568 CAAAUACCUUGAACCCUCGU 1569 CCAAAUACCUUGAACCCUCG 1570 ACCAAAUACCUUGAACCCUC 1571 AACCAAAUACCUUGAACCCU 1572 GAACCAAAUACCUUGAACCC 1573 UGAACCAAAUACCUUGAACC 1574 CCCUGAACCAAAUACCUUGA 1575 GGCCCUGAACCAAAUACCUU 1576 UGGCCCUGAACCAAAUACCU 1577 UAUUCAGGUUGUUGCCCAAA 1578 GGUAUUCAGGUUGUUGCCCA 1579 AGGUAUUCAGGUUGUUGCCC 1580 AAGGUAUUCAGGUUGUUGCC 1581 AAAGGUAUUCAGGUUGUUGC 1582 UAACUUGAUUGCCCUGUGAC 1583 GUAACUUGAUUGCCCUGUGA 1584 AGUAACUUGAUUGCCCUGUG 1585 CAGAGUAACUUGAUUGCCCU 1586 ACAGAGUAACUUGAUUGCCC 1587 CACAGAGUAACUUGAUUGCC 1588 UGUCCUGACAAAGAAACACA 1589 CAAUCCCUGCUUUCCUGCCA 1590 ACAAUCCCUGCUUUCCUGCC 1591 AACACAAUCCCUGCUUUCCU 1592 GAACACAAUCCCUGCUUUCC 1593 AAUGAACACAAUCCCUGCUU 1594 AAAUGAACACAAUCCCUGCU 1595 GUGAAACCCUCAAAUGAACA 1596 AGUGAAACCCUCAAAUGAAC 1597 CAGUGAAACCCUCAAAUGAA 1598 ACAGUGAAACCCUCAAAUGA 1599 GCAUGGAAGCUGAGACUCUC 1600 UUGCAUGGAAGCUGAGACUC 1601 CAGUUGCAUGGAAGCUGAGA 1602 ACAGUUGCAUGGAAGCUGAG 1603 GACAGUUGCAUGGAAGCUGA 1604 AUGGACAGUUGCAUGGAAGC 1605 GUGAUGGACAGUUGCAUGGA 1606 CGUGAUGGACAGUUGCAUGG 1607 CCGUGAUGGACAGUUGCAUG 1608 GCCGUGAUGGACAGUUGCAU 1609 AGCCGUGAUGGACAGUUGCA 1610 CAGCCGUGAUGGACAGUUGC 1611 GCAGCCGUGAUGGACAGUUG 1612 UGCAGCCGUGAUGGACAGUU 1613 UUGCAGCCGUGAUGGACAGU 1614 GUUGCAGCCGUGAUGGACAG 1615 CAGUUGCAGCCGUGAUGGAC 1616 UCAGUUGCAGCCGUGAUGGA 1617 UUCAGUUGCAGCCGUGAUGG 1618 UUUCAGUUGCAGCCGUGAUG 1619 AUUUCAGUUGCAGCCGUGAU 1620 GAUUUCAGUUGCAGCCGUGA 1621 UGAUUUCAGUUGCAGCCGUG 1622 CUCUGAUUUCAGUUGCAGCC 1623 UUAGCUUCUGGUGCGCUGUG 1624 UUUAGCUUCUGGUGCGCUGU 1625 CUUUAGCUUCUGGUGCGCUG 1626 GACUUUAGCUUCUGGUGCGC 1627 AGACUUUAGCUUCUGGUGCG 1628 AAGACUUUAGCUUCUGGUGC 1629 UCAAGACUUUAGCUUCUGGU 1630 AUCAAGACUUUAGCUUCUGG 1631 GCAUCAAGACUUUAGCUUCU 1632 AUGGCAUCAAGACUUUAGCU 1633 GAUGGCAUCAAGACUUUAGC 1634 AGGGAUGUCCUUUGAUGGCA 1635 GCAGGGAUGUCCUUUGAUGG 1636 GGCAGGGAUGUCCUUUGAUG 1637 CGUGACAGAGAUGUGAAUGG 1638 GGACGUGACAGAGAUGUGAA 1639 UGGACGUGACAGAGAUGUGA 1640 GUGGACGUGACAGAGAUGUG 1641 AGUGGACGUGACAGAGAUGU 1642 UAGUGGACGUGACAGAGAUG 1643 UUAGUGGACGUGACAGAGAU 1644 AUUAGUGGACGUGACAGAGA 1645 GAUUAGUGGACGUGACAGAG 1646 CGAUUAGUGGACGUGACAGA 1647 CCGAUUAGUGGACGUGACAG 1648 UGCCGAUUAGUGGACGUGAC 1649 UUGCCGAUUAGUGGACGUGA 1650 UUUGCCGAUUAGUGGACGUG 1651 UUUUGCCGAUUAGUGGACGU 1652 CUUUUGCCGAUUAGUGGACG 1653 CCUUUUGCCGAUUAGUGGAC 1654 UCCUUUUGCCGAUUAGUGGA 1655 CUCCUUUUGCCGAUUAGUGG 1656 UCUCCUUUUGCCGAUUAGUG 1657 UUCUCCUUUUGCCGAUUAGU 1658 UUUCUCCUUUUGCCGAUUAG 1659 AGGUCAUCUUCUCUCACUUU 1660 UUAGGUCAUCUUCUCUCACU 1661 CUUAGGUCAUCUUCUCUCAC 1662 ACACUUAGGUCAUCUUCUCU 1663 CACACUUAGGUCAUCUUCUC 1664 UCACACUUAGGUCAUCUUCU 1665 GUCACACUUAGGUCAUCUUC 1666 AGUCACACUUAGGUCAUCUU 1667 CAGUCACACUUAGGUCAUCU 1668 GCAGUCACACUUAGGUCAUC 1669 UGCAGUCACACUUAGGUCAU 1670 AUUUUCCAGAGCUGCCUGCU 1671 CUCACUGCUCUGGCUUCAUU 1672 GCUCACUGCUCUGGCUUCAU 1673 UUACCUGCUCUUUCCUUCCU 1674 UGCUUACCUGCUCUUUCCUU 1675 UUCCUGCUUACCUGCUCUUU 1676 CUUCCUGCUUACCUGCUCUU 1677 ACUGGCCUUCCUGCUUACCU 1678 GACACUGGCCUUCCUGCUUA 1679 CAUUAGGGUCCUGUCUGGGA 1680 UCAUUAGGGUCCUGUCUGGG 1681 AUCAUUAGGGUCCUGUCUGG 1682 GAUCAUUAGGGUCCUGUCUG 1683 GGAUCAUUAGGGUCCUGUCU 1684 AUUCAGGAUCAUUAGGGUCC 1685 GAUUCAGGAUCAUUAGGGUC 1686 GGAUUCAGGAUCAUUAGGGU 1687 AUGGAUUCAGGAUCAUUAGG 1688 GAUACAUGGAUUCAGGAUCA 1689 UGAUACAUGGAUUCAGGAUC 1690 AUGGCAGGGCUUUGGAAAAU 1691 CAUGGCAGGGCUUUGGAAAA 1692 GCAUGGCAGGGCUUUGGAAA 1693 CAGCAUGGCAGGGCUUUGGA 1694 GAAGUGGGAUGGCAGCAUGG 1695 GGAAGUGGGAUGGCAGCAUG 1696 GGGAAGUGGGAUGGCAGCAU 1697 UGGAGAAGCCAUAAGCUGCA 1698 CUGGAGAAGCCAUAAGCUGC 1699 ACUGGAGAAGCCAUAAGCUG 1700 UACUGGAGAAGCCAUAAGCU 1701 CUACUGGAGAAGCCAUAAGC 1702 CCUACUGGAGAAGCCAUAAG 1703 ACCUACUGGAGAAGCCAUAA 1704 CACCUACUGGAGAAGCCAUA 1705 CCACCUACUGGAGAAGCCAU 1706 GCCACCUACUGGAGAAGCCA 1707 CUGCCACCUACUGGAGAAGC 1708 GCUGCCACCUACUGGAGAAG 1709 UGUGUGUGCUGCCACCUACU 1710 CUGUGUGUGCUGCCACCUAC 1711 UUAUGAGUGGCUCUGUGUGU 1712 UUUAUGAGUGGCUCUGUGUG 1713 AGUUUAUGAGUGGCUCUGUG 1714 CAGUUUAUGAGUGGCUCUGU 1715 GUUUCUGGCUCUCAGGCUCU 1716 GGUUUCUGGCUCUCAGGCUC 1717 CGGUUUCUGGCUCUCAGGCU 1718 GGACGGUUUCUGGCUCUCAG 1719 GGGACGGUUUCUGGCUCUCA 1720 UGAAAUGUGACUUCUGGUGU 1721 GGGAACCAUGUAAAAGGAUG 1722 GUGAGGGUAGAUGGGAACCA 1723 UUGUGAGGGUAGAUGGGAAC 1724 GUUGUGAGGGUAGAUGGGAA 1725 UGUUGUGAGGGUAGAUGGGA 1726 AUGUGUGUCUUUGGUGAUGA 1727 GGAGCUUGUAUGUGUGUCUU 1728 UUGGAGCUUGUAUGUGUGUC 1729 AUUGGAGCUUGUAUGUGUGU 1730 CAUUGGAGCUUGUAUGUGUG 1731 CCAUUGGAGCUUGUAUGUGU 1732 GCCAUUGGAGCUUGUAUGUG 1733 AGCCAUUGGAGCUUGUAUGU 1734 CUGGAGGAAGAAUUGCCUGG 1735 GUCCUGGAGGAAGAAUUGCC 1736 GCCAGUAAGAAGGGCAAAGU 1737 GGCCAGUAAGAAGGGCAAAG 1738 GGAAUGAGUCAAGCCUGGAC 1739 GGGAAUGAGUCAAGCCUGGA 1740 GUGGGAAUGAGUCAAGCCUG 1741 AAGGUGGGAAUGAGUCAAGC 1742 UCUCAGCCCAGGACAAGGUG 1743 AUCUCAGCCCAGGACAAGGU 1744 GCUGGGUGGUUCUCUCCUGU 1745 UUCUGGGCUGGGUGGUUCUC 1746 GAACUUCUGGGCUGGGUGGU 1747 CGGAGAGUUCCUUCCCUGGA 1748 ACCGGAGAGUUCCUUCCCUG 1749 GACCGGAGAGUUCCUUCCCU 1750 UGGACCGGAGAGUUCCUUCC 1751 GUGGACCGGAGAGUUCCUUC 1752 GGUGGACCGGAGAGUUCCUU 1753 UGGUGGACCGGAGAGUUCCU 1754 AUGGUGGACCGGAGAGUUCC 1755 CAUGGUGGACCGGAGAGUUC 1756 GAGCUGAGAGGUACUCCAUG 1757 AGAGCUGAGAGGUACUCCAU 1758 CAGAGCUGAGAGGUACUCCA 1759 UUCAGAGCUGAGAGGUACUC 1760 GGUUCAGAGCUGAGAGGUAC 1761 GGGUUCAGAGCUGAGAGGUA 1762 CACCUGAGUAAGUCACUGGG 1763 UCACCUGAGUAAGUCACUGG 1764 GUCACCUGAGUAAGUCACUG 1765 AGUCACCUGAGUAAGUCACU 1766 CAGUCACCUGAGUAAGUCAC 1767 GCAGUCACCUGAGUAAGUCA 1768 UUAGCAGUCACCUGAGUAAG 1769 GUUAGCAGUCACCUGAGUAA 1770 GGUUAGCAGUCACCUGAGUA 1771 GGGUUAGCAGUCACCUGAGU 1772 AGGGUUAGCAGUCACCUGAG 1773 GAGGGUUAGCAGUCACCUGA 1774 GGAGGGUUAGCAGUCACCUG 1775 CGGAGGGUUAGCAGUCACCU 1776 AGCGGAGGGUUAGCAGUCAC 1777 GAGCGGAGGGUUAGCAGUCA 1778 AGAGCGGAGGGUUAGCAGUC 1779 UAGAGCGGAGGGUUAGCAGU 1780 GUAGAGCGGAGGGUUAGCAG 1781 GGUAGAGCGGAGGGUUAGCA 1782 AGGGUAGAGCGGAGGGUUAG 1783 GAGGGUAGAGCGGAGGGUUA 1784 AUUGUUGCCCUGCCUAUAUC 1785 AGUAUUGUUGCCCUGCCUAU 1786 GAGUAUUGUUGCCCUGCCUA 1787 GGAGUAUUGUUGCCCUGCCU 1788 UGGAGUAUUGUUGCCCUGCC 1789 GUGGAGUAUUGUUGCCCUGC 1790 AGUGGAGUAUUGUUGCCCUG 1791 GAGUGGAGUAUUGUUGCCCU 1792 UGAGUGGAGUAUUGUUGCCC 1793 CUGAGUGGAGUAUUGUUGCC 1794 GCUGAGUGGAGUAUUGUUGC 1795 GGCUGAGUGGAGUAUUGUUG 1796 GGGCUGAGUGGAGUAUUGUU 1797 GGUACUGGUUAGUCUCCUAG 1798 GGGUACUGGUUAGUCUCCUA 1799 UUGACAAGCCCACUGUGGAG 1800 UGGCUCAGGAGCUUGACAAG 1801 GGUGGCUCAGGAGCUUGACA 1802 UAGGGAUGAGGGAGAGACCA 1803 UCGAUUAGGGAUGAGGGAGA 1804 UAGAGGGCUAGGGAGGGAGA 1805 GUAGAGUGGCUAGAGGGCUA 1806 GGUAGAGUGGCUAGAGGGCU 1807 UGAGGGUAGAGUGGCUAGAG 1808 GAUGAGGGUAGAGUGGCUAG 1809 CAUGAUGAGGGUAGAGUGGC 1810 GCAUGAUGAGGGUAGAGUGG 1811 GGGCAUGAUGAGGGUAGAGU 1812 GGUAGUUGAGAAGAAAAGUC 1813 CCAAACUCCGAGCUUAUAUU 1814 UCCAAACUCCGAGCUUAUAU 1815 GUCCAAACUCCGAGCUUAUA 1816 CGUCCAAACUCCGAGCUUAU 1817 CCGUCCAAACUCCGAGCUUA 1818 UCCGUCCAAACUCCGAGCUU 1819 CUCCGUCCAAACUCCGAGCU 1820 ACCCUCCGUCCAAACUCCGA 1821 AGACCCUCCGUCCAAACUCC 1822 CAGACCCUCCGUCCAAACUC 1823 UCCAGACCCUCCGUCCAAAC 1824 GUCCAGACCCUCCGUCCAAA 1825 AGACACGGAAAGGUCGCUGG 1826 CAGACACGGAAAGGUCGCUG 1827 ACAGACACGGAAAGGUCGCU 1828 CACAGACACGGAAAGGUCGC 1829 UCACAGACACGGAAAGGUCG 1830 AUCACAGACACGGAAAGGUC 1831 GAUCACAGACACGGAAAGGU 1832 UUGGCCUACUUACUUUGGCU 1833 CUUGGCCUACUUACUUUGGC 1834 ACUUGGCCUACUUACUUUGG 1835 GAGGAACUUGGCCUACUUAC 1836 CGAGGAACUUGGCCUACUUA 1837 CCGAGGAACUUGGCCUACUU 1838 ACCGAGGAACUUGGCCUACU 1839 AACCGAGGAACUUGGCCUAC 1840 GAACCGAGGAACUUGGCCUA 1841 GGAACCGAGGAACUUGGCCU 1842 AGGAACCGAGGAACUUGGCC 1843 UAGGAACCGAGGAACUUGGC 1844 AUAGGAACCGAGGAACUUGG 1845 UAUAGGAACCGAGGAACUUG 1846 AUCACAAGUUGCCACUGUUG 1847 CAUCACAAGUUGCCACUGUU 1848 AUCAUCACAAGUUGCCACUG 1849 CAUCAUCACAAGUUGCCACU 1850 CUGCUCCAUCAUCACAAGUU 1851 UCUGCUCCAUCAUCACAAGU 1852 CCCUCUGCUCCAUCAUCACA 1853 UCAGCCCUCUGCUCCAUCAU 1854 UGACUUCAGCCCUCUGCUCC 1855 GUGACUUCAGCCCUCUGCUC 1856 UGUGACUUCAGCCCUCUGCU 1857 GUGUGACUUCAGCCCUCUGC 1858 UGUGUGACUUCAGCCCUCUG 1859 GCCCACUCCGCUGCUUUUAG 1860 GGCCCACUCCGCUGCUUUUA 1861 AGGCCCACUCCGCUGCUUUU 1862 UAGGCCCACUCCGCUGCUUU 1863 UUAGGCCCACUCCGCUGCUU 1864 AUUAGGCCCACUCCGCUGCU 1865 UCAUUAGGCCCACUCCGCUG 1866 CUCAUUAGGCCCACUCCGCU 1867 AGCUCAUUAGGCCCACUCCG 1868 CUCCCAUAGAAAAGCUCACU 1869 GCUCCCAUAGAAAAGCUCAC 1870 UGCUCCCAUAGAAAAGCUCA 1871 CUGCUCCCAUAGAAAAGCUC 1872 CCUGCUCCCAUAGAAAAGCU 1873 UCCCUAUCUCCUGCUAACCC 1874 CCUCGAACUCUCCCUAUCUC 1875 CCCUCGAACUCUCCCUAUCU 1876 UCCCUCGAACUCUCCCUAUC 1877 GUCCCUCGAACUCUCCCUAU 1878 CUUUCCAUACUAGCUUCUGA 1879 CCUUUCCAUACUAGCUUCUG 1880 ACCUUUCCAUACUAGCUUCU 1881 CACACAAAUCACCUUUCCAU 1882 GUCACACAAAUCACCUUUCC 1883 UGUCACACAAAUCACCUUUC 1884 UUUGACAGGCAGGAAGUGGC 1885 GGUUUGACAGGCAGGAAGUG 1886 AGGUUUGACAGGCAGGAAGU 1887 AAGGUUUGACAGGCAGGAAG 1888 AACUUCCCAAGGUUUGACAG 1889 CAACUUCCCAAGGUUUGACA 1890 GAACAACUUCCCAAGGUUUG 1891 UGAACAACUUCCCAAGGUUU 1892 GUAGGUUGAACAACUUCCCA 1893 GGUAGGUUGAACAACUUCCC 1894 UGGUAGGUUGAACAACUUCC 1895 GGUUUUGGUAGGUUGAACAA 1896 UGAGGUUUUGGUAGGUUGAA 1897 CUGAGGUUUUGGUAGGUUGA 1898 CCUACAUUAUCCUCUUACUC 1899 GGACUUUACCUACAUUAUCC 1900 GUAUGAGGACUUUACCUACA 1901 GCCAGGUAUGAGGACUUUAC 1902 UGCCAGGUAUGAGGACUUUA 1903 GUGCCAGGUAUGAGGACUUU 1904 CUGUGCCAGGUAUGAGGACU 1905 UCUGUGCCAGGUAUGAGGAC 1906 CCUCAAGAGUUCUCCAGAAG 1907 CCCUCAAGAGUUCUCCAGAA 1908 ACCCUCAAGAGUUCUCCAGA 1909 ACACCCUCAAGAGUUCUCCA 1910 CACACCCUCAAGAGUUCUCC 1911 CCACACCCUCAAGAGUUCUC 1912 CCCACACCCUCAAGAGUUCU 1913 UUCCCACACCCUCAAGAGUU 1914 CAAUGCUGCACCUCACUUCC 1915 UACAAUGCUGCACCUCACUU 1916 CUACAAUGCUGCACCUCACU 1917 UCUACAAUGCUGCACCUCAC 1918 AUCUACAAUGCUGCACCUCA 1919 UAUCUACAAUGCUGCACCUC 1920 CUUAUCUACAAUGCUGCACC 1921 GUCUUAUCUACAAUGCUGCA 1922 UGUCUUAUCUACAAUGCUGC 1923 CUGUCUUAUCUACAAUGCUG 1924 CACCCUUCUGUCUUAUCUAC 1925 UCCACCCUUCUGUCUUAUCU 1926 GUCCACCCUUCUGUCUUAUC 1927 AGUCCACCCUUCUGUCUUAU 1928 AAGUCCACCCUUCUGUCUUA 1929 GAAAGCAAGCCAGGUUCUCA 1930 GGAAAGCAAGCCAGGUUCUC 1931 GGAAUUGGAAAGCAAGCCAG 1932 ACCAUGUCAUUGGCAUCUCC 1933 UACCAUGUCAUUGGCAUCUC 1934 CCUACCAUGUCAUUGGCAUC 1935 UCCUACCAUGUCAUUGGCAU 1936 CUCCUACCAUGUCAUUGGCA 1937 GCUCCUACCAUGUCAUUGGC 1938 UGCUCCUACCAUGUCAUUGG 1939 UCUUUGCUCCUACCAUGUCA 1940 CCUCUUUGCUCCUACCAUGU 1941 UUCCUCUUUGCUCCUACCAU 1942 UCUCCGUGUUCUUCAGUUUU 1943 CUCUCCGUGUUCUUCAGUUU 1944 AGCUCUCCGUGUUCUUCAGU 1945 UGCAGCUCUCCGUGUUCUUC 1946 GGUUGCAGCUCUCCGUGUUC 1947 AGGUUGCAGCUCUCCGUGUU 1948 AAAGGUUGCAGCUCUCCGUG 1949 UAAAGGUUGCAGCUCUCCGU 1950 CUAAAGGUUGCAGCUCUCCG 1951 CCUAAAGGUUGCAGCUCUCC 1952 UCCUAAAGGUUGCAGCUCUC 1953 CUCCUAAAGGUUGCAGCUCU 1954 CCUCCUAAAGGUUGCAGCUC 1955 GCACUUUGAUACCUCCUAAA 1956 GGCACUUUGAUACCUCCUAA 1957 GAUGUCCCACUUUGACUUUC 1958 UCGAUGUCCCACUUUGACUU 1959 GUCGAUGUCCCACUUUGACU 1960 GGUCGAUGUCCCACUUUGAC 1961 UGGUCGAUGUCCCACUUUGA 1962 UUGGUCGAUGUCCCACUUUG 1963 AUUGGUCGAUGUCCCACUUU 1964 CAUUGGUCGAUGUCCCACUU 1965 AACAUCCAUCAGUUGGCUCU 1966 CUGCCCAACAUCCAUCAGUU 1967 AGCUGCCCAACAUCCAUCAG 1968 UAGCUGCCCAACAUCCAUCA 1969 UUAGCUGCCCAACAUCCAUC 1970 UUUAGCUGCCCAACAUCCAU 1971 CUUUAGCUGCCCAACAUCCA 1972 CCUCUUUAGCUGCCCAACAU 1973 CCCUCUUUAGCUGCCCAACA 1974 UCCCUCUUUAGCUGCCCAAC 1975 UUCCCUCUUUAGCUGCCCAA 1976 CCUUCCCUCUUUAGCUGCCC 1977 CCCUUCCCUCUUUAGCUGCC 1978 GCAGGUCUUAUCCCAUGCCC 1979 GGGCAGGUCUUAUCCCAUGC 1980 AGGGCAGGUCUUAUCCCAUG 1981 AAGGGCAGGUCUUAUCCCAU 1982 GAAGGGCAGGUCUUAUCCCA 1983 AGAAGGGCAGGUCUUAUCCC 1984 CCAAUGGCAAGAAGCAAGAA 1985 CCCAAUGGCAAGAAGCAAGA 1986 GCCCAAUGGCAAGAAGCAAG 1987 UCCAAUGCCUGCCCAAUGGC 1988 CUCCAAUGCCUGCCCAAUGG 1989 UCUCCAAUGCCUGCCCAAUG 1990 GGUCUCCAAUGCCUGCCCAA 1991 UAGGGUCUCCAAUGCCUGCC 1992 GUAGGGUCUCCAAUGCCUGC 1993 AGUAGGGUCUCCAAUGCCUG 1994 CAGUAGGGUCUCCAAUGCCU 1995 GCAGUAGGGUCUCCAAUGCC 1996 AGCAGUAGGGUCUCCAAUGC 1997 CAGCAGUAGGGUCUCCAAUG 1998 UCAGCAGUAGGGUCUCCAAU 1999 AUUCAGCAGUAGGGUCUCCA 2000 CAUUCAGCAGUAGGGUCUCC 2001 CCAUUCAGCAGUAGGGUCUC 2002 UCCAUUCAGCAGUAGGGUCU 2003 ACUCCAUUCAGCAGUAGGGU 2004 CACUCCAUUCAGCAGUAGGG 2005 GCACUCCAUUCAGCAGUAGG 2006 AGCACUCCAUUCAGCAGUAG 2007 UAGCACUCCAUUCAGCAGUA 2008 GUUAGCACUCCAUUCAGCAG 2009 GGUUAGCACUCCAUUCAGCA 2010 GGGUUAGCACUCCAUUCAGC 2011 CAGGGUUAGCACUCCAUUCA 2012 CCAGGGUUAGCACUCCAUUC 2013 ACCAGGGUUAGCACUCCAUU 2014 CACCAGGGUUAGCACUCCAU 2015 GCACCAGGGUUAGCACUCCA 2016 AGCACCAGGGUUAGCACUCC 2017 UAGCACCAGGGUUAGCACUC 2018 CUAGCACCAGGGUUAGCACU 2019 UCUAGCACCAGGGUUAGCAC 2020 CUCUAGCACCAGGGUUAGCA 2021 CCUCUAGCACCAGGGUUAGC 2022 UCCUCUAGCACCAGGGUUAG 2023 CUCCUCUAGCACCAGGGUUA 2024 CCUCCUCUAGCACCAGGGUU 2025 UCCUCCUCUAGCACCAGGGU 2026 GUUCCAUCCUCCUCUAGCAC 2027 AAGUCCUCACUGUCCACUGC 2028 GAAGUCCUCACUGUCCACUG 2029 AGAAGUCCUCACUGUCCACU 2030 AAGAAGUCCUCACUGUCCAC 2031 GAAGAAGUCCUCACUGUCCA 2032 GGAAGAAGUCCUCACUGUCC 2033 UGGAAGAAGUCCUCACUGUC 2034 CUGGAAGAAGUCCUCACUGU 2035 AGCUGGAAGAAGUCCUCACU 2036 ACUGCAACACCAUCAGGCAC 2037 GACUGCAACACCAUCAGGCA 2038 AGACUGCAACACCAUCAGGC 2039 CAGACUGCAACACCAUCAGG 2040 CCAGACUGCAACACCAUCAG 2041 GACCAGACUGCAACACCAUC 2042 CUCUGACCAGACUGCAACAC 2043 AGCUCUGACCAGACUGCAAC 2044 CCAGCUCUGACCAGACUGCA 2045 UGUAGGGCUCCAGCUCUGAC 2046 CUUGUAGGGCUCCAGCUCUG 2047 CCUUGUAGGGCUCCAGCUCU 2048 ACAGGCAUUGGAAGCAGCCC 2049 GACAGGCAUUGGAAGCAGCC 2050 AAGGACAGGCAUUGGAAGCA 2051 AAAGGACAGGCAUUGGAAGC 2052 UAAAGGACAGGCAUUGGAAG 2053 CUAAAGGACAGGCAUUGGAA 2054 GCUCUAAAGGACAGGCAUUG 2055 AGCUCUAAAGGACAGGCAUU 2056 AAGCUCUAAAGGACAGGCAU 2057 AAAGCUCUAAAGGACAGGCA 2058 GAAAGCUCUAAAGGACAGGC 2059 CGGGAAAGCUCUAAAGGACA 2060 CCGGGAAAGCUCUAAAGGAC 2061 AGGGUUAAGCUAGAGAGGAA 2062 UCAGGGUUAAGCUAGAGAGG 2063 GAUCAGGGUUAAGCUAGAGA 2064 GGAUCAGGGUUAAGCUAGAG 2065 AGGAUCAGGGUUAAGCUAGA 2066 CCCAGGAUCAGGGUUAAGCU 2067 CAACUCCUCCUGCACCUGGU 2068 ACAACUCCUCCUGCACCUGG 2069 GACAAUUCCACAACUCCUCC 2070 UGACAAUUCCACAACUCCUC 2071 UUGACAAUUCCACAACUCCU 2072 CUUGACAAUUCCACAACUCC 2073 UCCUUGACAAUUCCACAACU 2074 AUCCUUGACAAUUCCACAAC 2075 CAUCCUUGACAAUUCCACAA 2076 ACAUCCUUGACAAUUCCACA 2077 GACAUCCUUGACAAUUCCAC 2078 UGACAUCCUUGACAAUUCCA 2079 UGUGUGACAUCCUUGACAAU 2080 ACUGUGUGACAUCCUUGACA 2081 ACUUUCUGUCCACUGUGUGA 2082 CCUCGCUUGGACUUUCUGUC 2083 CCCUCGCUUGGACUUUCUGU 2084 UCCCUCGCUUGGACUUUCUG 2085 CUCCCUCGCUUGGACUUUCU 2086 CCUCCCUCGCUUGGACUUUC 2087 CCCUCCCUCGCUUGGACUUU 2088 UCCAUCAGCACUGGGUCAGA 2089 ACCACUAAUCUCCAUCAGCA 2090 CACCACUAAUCUCCAUCAGC 2091 CCACCACUAAUCUCCAUCAG 2092 CCCACCACUAAUCUCCAUCA 2093 ACCAGACACCCACCACUAAU 2094 UACCAGACACCCACCACUAA 2095 CUCAUACCAGACACCCACCA 2096 CCUCAUACCAGACACCCACC 2097 UCCUCAUACCAGACACCCAC 2098 AUCCUCAUACCAGACACCCA 2099 GAUCCUCAUACCAGACACCC 2100 AGAUCCUCAUACCAGACACC 2101 UAGAUCCUCAUACCAGACAC 2102 GUAGAUCCUCAUACCAGACA 2103 AGUAGAUCCUCAUACCAGAC 2104 CAGUAGAUCCUCAUACCAGA 2105 UGCAGUAGAUCCUCAUACCA 2106 GUGCAGUAGAUCCUCAUACC 2107 AGUGCAGUAGAUCCUCAUAC 2108 ACUCUGUAGGACACCCUUGU 2109 CACUCUGUAGGACACCCUUG 2110 CCACUCUGUAGGACACCCUU 2111 UCCACUCUGUAGGACACCCU 2112 CUCCACUCUGUAGGACACCC 2113 ACUCCACUCUGUAGGACACC 2114 CACUCCACUCUGUAGGACAC 2115 AGCACUCCACUCUGUAGGAC 2116 UAUGACAGCACUCCACUCUG 2117 AUAUGACAGCACUCCACUCU 2118 UUGCUGUGCUUGGGCCUCUC 2119 ACGUCAAAGGUGAAUCGGGC 2120 CACGUCAAAGGUGAAUCGGG 2121 ACACGUCAAAGGUGAAUCGG 2122 UACACGUCAAAGGUGAAUCG 2123 GUACACGUCAAAGGUGAAUC 2124 GGCUGCCAAAGAGGUCUCGA 2125 UCAGGCUGCCAAAGAGGUCU 2126 CAUUCAGGCUGCCAAAGAGG 2127 GACAUUCAGGCUGCCAAAGA 2128 UGACAUUCAGGCUGCCAAAG 2129 CUUUGACAUUCAGGCUGCCA 2130 GCUUUGACAUUCAGGCUGCC 2131 CCGUAGAAUGUGGCUUUGAC 2132 GCCCGUAGAAUGUGGCUUUG 2133 UAGAGCCCGUAGAAUGUGGC 2134 GUAGAGCCCGUAGAAUGUGG 2135 AGUAGAGCCCGUAGAAUGUG 2136 AGAGUAGAGCCCGUAGAAUG 2137 UAGAGUAGAGCCCGUAGAAU 2138 AUAGAGUAGAGCCCGUAGAA 2139 CAUAGAGUAGAGCCCGUAGA 2140 UCAUAGAGUAGAGCCCGUAG 2141 CUCAUAGAGUAGAGCCCGUA 2142 GAAAGUCACAACUCAUAGAG 2143 CCUUGAAAGUCACAACUCAU 2144 AAGUCCUUGAAAGUCACAAC 2145 CCAAGUCCUUGAAAGUCACA 2146 UUCUUUGGGCCAAGUCCUUG 2147 UUUCUUUGGGCCAAGUCCUU 2148 UUGAUUUCUGACCUGAGUAC 2149 GUUGAUUUCUGACCUGAGUA 2150 GGGACUAUCCAACUGUAGGG 2151 GCAAGAGGACGAAUUAUGGG 2152 UGCAAGAGGACGAAUUAUGG 2153 GUGCAAGAGGACGAAUUAUG 2154 GGUGCAAGAGGACGAAUUAU 2155 GGGUGCAAGAGGACGAAUUA 2156 UGGGUGCAAGAGGACGAAUU 2157 GUGGGUGCAAGAGGACGAAU 2158 GGUGGGUGCAAGAGGACGAA 2159 UAGGUGGGUGCAAGAGGACG 2160 GUAGGUGGGUGCAAGAGGAC 2161 GGUAGGUGGGUGCAAGAGGA 2162 CCACAAGCAAGAGCUAACUA 2163 ACUUUCCACAAGCAAGAGCU 2164 GACUUUCCACAAGCAAGAGC 2165 GGACUUUCCACAAGCAAGAG 2166 AGGACUUUCCACAAGCAAGA 2167 GAGGACUUUCCACAAGCAAG 2168 UGAGGACUUUCCACAAGCAA 2169 AUGAGGACUUUCCACAAGCA 2170 GAUGAGGACUUUCCACAAGC 2171 AGAUGAGGACUUUCCACAAG 2172 GAGAUGAGGACUUUCCACAA 2173 GGAGAUGAGGACUUUCCACA 2174 UGGGAGAUGAGGACUUUCCA 2175 GCUGGGAGAUGAGGACUUUC 2176 UCAAGCUGGGAGAUGAGGAC 2177 AAGCCAUCAAGCUGGGAGAU 2178 GAAGCCAUCAAGCUGGGAGA 2179 GGAGGAAGCCAUCAAGCUGG 2180 GGGAGGAAGCCAUCAAGCUG 2181 AACUUGGGAGGAAGCCAUCA 2182 AAACUUGGGAGGAAGCCAUC 2183 CAGCAGUGUGGAGGUCCAAC 2184 GCAGCAGUGUGGAGGUCCAA 2185 UGCAGCAGUGUGGAGGUCCA 2186 UUGCAGCAGUGUGGAGGUCC 2187 GGUGGAGGAAAUUCCCAGCA 2188 ACGAAGGGUGGAGGAAAUUC 2189 GACGAAGGGUGGAGGAAAUU 2190 AUGACGAAGGGUGGAGGAAA 2191 CAUGACGAAGGGUGGAGGAA 2192 GCAUGACGAAGGGUGGAGGA 2193 UGCAUGACGAAGGGUGGAGG 2194 CUGCAUGACGAAGGGUGGAG 2195 ACUGCAUGACGAAGGGUGGA 2196 CACUGCAUGACGAAGGGUGG 2197 CCACUGCAUGACGAAGGGUG 2198 UCCACUGCAUGACGAAGGGU 2199 CUCCACUGCAUGACGAAGGG 2200 CCUCCACUGCAUGACGAAGG 2201 CCCUCCACUGCAUGACGAAG 2202 CUUAGUAGGAAUGGAGGCGG 2203 CCUUAGUAGGAAUGGAGGCG 2204 CCCUUAGUAGGAAUGGAGGC 2205 UCGGUUGGAAUGAUUCUGGG 2206 GUCGGUUGGAAUGAUUCUGG 2207 GGUCGGUUGGAAUGAUUCUG 2208 GGGUCGGUUGGAAUGAUUCU 2209 UGGGUCGGUUGGAAUGAUUC 2210 GUGGGUCGGUUGGAAUGAUU 2211 AGUGGGUCGGUUGGAAUGAU 2212 CAGUGGGUCGGUUGGAAUGA 2213 GCAGUGGGUCGGUUGGAAUG 2214 UGCAGUGGGUCGGUUGGAAU 2215 UUGCAGUGGGUCGGUUGGAA 2216 UUUGCAGUGGGUCGGUUGGA 2217 CUUUGCAGUGGGUCGGUUGG 2218 UCUUUGCAGUGGGUCGGUUG 2219 UAGUCUUUGCAGUGGGUCGG 2220 AUAGUCUUUGCAGUGGGUCG 2221 CUGUCAUAGUCUUUGCAGUG 2222 UGCUGUCAUAGUCUUUGCAG 2223 UCUAGCCUGUACUGUCUGCA 2224 AUCUAGCCUGUACUGUCUGC 2225 UAUCUAGCCUGUACUGUCUG 2226 UUAUCUAGCCUGUACUGUCU 2227 GUUAUCUAGCCUGUACUGUC 2228 GGUUAUCUAGCCUGUACUGU 2229 GGGUUAUCUAGCCUGUACUG 2230 UGGGUUAUCUAGCCUGUACU 2231 GUGGGUUAUCUAGCCUGUAC 2232 GGUGGGUUAUCUAGCCUGUA 2233 GGGUGGGUUAUCUAGCCUGU 2234 UGGGUGGGUUAUCUAGCCUG 2235 UUGGGUGGGUUAUCUAGCCU 2236 AUUGGGUGGGUUAUCUAGCC 2237 AAUUGGGUGGGUUAUCUAGC 2238 AAAUUGGGUGGGUUAUCUAG 2239 GGAAAUUGGGUGGGUUAUCU 2240 GGGAAAUUGGGUGGGUUAUC 2241 GAAAGGUUCUGUCACGAGGG 2242 GCUGAAAGGUUCUGUCACGA 2243 UGCUGAAAGGUUCUGUCACG 2244 GGCGUUAUGCUGAAAGGUUC 2245 AGGCGUUAUGCUGAAAGGUU 2246 GAGGCGUUAUGCUGAAAGGU 2247 UGAGGCGUUAUGCUGAAAGG 2248 GUGAGGCGUUAUGCUGAAAG 2249 AUGUGAGGCGUUAUGCUGAA 2250 GAUGUGAGGCGUUAUGCUGA 2251 GGAUGUGAGGCGUUAUGCUG 2252 GGGAUGUGAGGCGUUAUGCU 2253 CUUGGGAUGUGAGGCGUUAU 2254 AGACUUGGGAUGUGAGGCGU 2255 UAGACUUGGGAUGUGAGGCG 2256 AUAGACUUGGGAUGUGAGGC 2257 UAUAGACUUGGGAUGUGAGG 2258 GGGUAUAGACUUGGGAUGUG 2259 AGGGUAUAGACUUGGGAUGU 2260 AAGGUGGCUAGGAAAGAACA 2261 AAAGGUGGCUAGGAAAGAAC 2262 GAAAGGUGGCUAGGAAAGAA 2263 ACAUCUUGAUCUUGGCCUUU 2264 GGCUGGGAUCAAGAUGCCUG 2265 GUCAGGCUGGGAUCAAGAUG 2266 AGUCAGGCUGGGAUCAAGAU 2267 CAGUCAGGCUGGGAUCAAGA 2268 AGCAGUCAGGCUGGGAUCAA 2269 GAUGUAGCAGCAGUCAGGCU 2270 GGAUUAGAUGUAGCAGCAGU 2271 GGGAUUAGAUGUAGCAGCAG 2272 GACAGGAGGCAUUGGUAGGG 2273 UUAGGGACAGGAGGCAUUGG 2274 UUUAGGGACAGGAGGCAUUG 2275 GAGUUUAGGGACAGGAGGCA 2276 GGAGUUUAGGGACAGGAGGC 2277 GCUGUCAUCAGUAUGCUGGG 2278 GGCUGUCAUCAGUAUGCUGG 2279 GGGCUGUCAUCAGUAUGCUG 2280 AGGGCUGUCAUCAGUAUGCU 2281 AGAGAGGGCUGUCAUCAGUA 2282 CAGAGAGGGCUGUCAUCAGU 2283 UCAGAGAGGGCUGUCAUCAG 2284 GUCAGAGAGGGCUGUCAUCA 2285 GGUAAAGUCAGAGAGGGCUG 2286 GGGAAGGGUAUGAAGACAGA 2287

In some embodiments, the antisense nucleic acid molecules targeted to Transcript C comprise or consist of the nucleotide sequences shown in Table 4.

TABLE 4 SEQ ID Sequence NO: GUUUCUGGCUCUCAGGCUCU 2288 GGUUUCUGGCUCUCAGGCUC 2289 CGGUUUCUGGCUCUCAGGCU 2290 GGACGGUUUCUGGCUCUCAG 2291 GGGACGGUUUCUGGCUCUCA 2292 UGAAAUGUGACUUCUGGUGU 2293 GGGAACCAUGUAAAAGGAUG 2294 GUGAGGGUAGAUGGGAACCA 2295 UUGUGAGGGUAGAUGGGAAC 2296 GUUGUGAGGGUAGAUGGGAA 2297 UGUUGUGAGGGUAGAUGGGA 2298 AUGUGUGUCUUUGGUGAUGA 2299 GGAGCUUGUAUGUGUGUCUU 2300 UUGGAGCUUGUAUGUGUGUC 2301 AUUGGAGCUUGUAUGUGUGU 2302 CAUUGGAGCUUGUAUGUGUG 2303 CCAUUGGAGCUUGUAUGUGU 2304 GCCAUUGGAGCUUGUAUGUG 2305 AGCCAUUGGAGCUUGUAUGU 2306 CUGGAGGAAGAAUUGCCUGG 2307 GUCCUGGAGGAAGAAUUGCC 2308 GCCAGUAAGAAGGGCAAAGU 2309 GGCCAGUAAGAAGGGCAAAG 2310 GGAAUGAGUCAAGCCUGGAC 2311 GGGAAUGAGUCAAGCCUGGA 2312 GUGGGAAUGAGUCAAGCCUG 2313 AAGGUGGGAAUGAGUCAAGC 2314 UCUCAGCCCAGGACAAGGUG 2315 AUCUCAGCCCAGGACAAGGU 2316 GCUGGGUGGUUCUCUCCUGU 2317 UUCUGGGCUGGGUGGUUCUC 2318 GAACUUCUGGGCUGGGUGGU 2319 CGGAGAGUUCCUUCCCUGGA 2320 ACCGGAGAGUUCCUUCCCUG 2321 GACCGGAGAGUUCCUUCCCU 2322 UGGACCGGAGAGUUCCUUCC 2323 GUGGACCGGAGAGUUCCUUC 2324 GGUGGACCGGAGAGUUCCUU 2325 UGGUGGACCGGAGAGUUCCU 2326 AUGGUGGACCGGAGAGUUCC 2327 CAUGGUGGACCGGAGAGUUC 2328 GAGCUGAGAGGUACUCCAUG 2329 AGAGCUGAGAGGUACUCCAU 2330 CAGAGCUGAGAGGUACUCCA 2331 UUCAGAGCUGAGAGGUACUC 2332 GGUUCAGAGCUGAGAGGUAC 2333 GGGUUCAGAGCUGAGAGGUA 2334 CACCUGAGUAAGUCACUGGG 2335 UCACCUGAGUAAGUCACUGG 2336 GUCACCUGAGUAAGUCACUG 2337 AGUCACCUGAGUAAGUCACU 2338 CAGUCACCUGAGUAAGUCAC 2339 GCAGUCACCUGAGUAAGUCA 2340 UUAGCAGUCACCUGAGUAAG 2341 GUUAGCAGUCACCUGAGUAA 2342 GGUUAGCAGUCACCUGAGUA 2343 GGGUUAGCAGUCACCUGAGU 2344 AGGGUUAGCAGUCACCUGAG 2345 GAGGGUUAGCAGUCACCUGA 2346 GGAGGGUUAGCAGUCACCUG 2347 CGGAGGGUUAGCAGUCACCU 2348 AGCGGAGGGUUAGCAGUCAC 2349 GAGCGGAGGGUUAGCAGUCA 2350 AGAGCGGAGGGUUAGCAGUC 2351 UAGAGCGGAGGGUUAGCAGU 2352 GUAGAGCGGAGGGUUAGCAG 2353 GGUAGAGCGGAGGGUUAGCA 2354 AGGGUAGAGCGGAGGGUUAG 2355 GAGGGUAGAGCGGAGGGUUA 2356 AUUGUUGCCCUGCCUAUAUC 2357 AGUAUUGUUGCCCUGCCUAU 2358 GAGUAUUGUUGCCCUGCCUA 2359 GGAGUAUUGUUGCCCUGCCU 2360 UGGAGUAUUGUUGCCCUGCC 2361 GUGGAGUAUUGUUGCCCUGC 2362 AGUGGAGUAUUGUUGCCCUG 2363 GAGUGGAGUAUUGUUGCCCU 2364 UGAGUGGAGUAUUGUUGCCC 2365 CUGAGUGGAGUAUUGUUGCC 2366 GCUGAGUGGAGUAUUGUUGC 2367 GGCUGAGUGGAGUAUUGUUG 2368 GGGCUGAGUGGAGUAUUGUU 2369 GGUACUGGUUAGUCUCCUAG 2370 GGGUACUGGUUAGUCUCCUA 2371 UUGACAAGCCCACUGUGGAG 2372 UGGCUCAGGAGCUUGACAAG 2373 GGUGGCUCAGGAGCUUGACA 2374 UAGGGAUGAGGGAGAGACCA 2375 UCGAUUAGGGAUGAGGGAGA 2376 UAGAGGGCUAGGGAGGGAGA 2377 GUAGAGUGGCUAGAGGGCUA 2378 GGUAGAGUGGCUAGAGGGCU 2379 UGAGGGUAGAGUGGCUAGAG 2380 GAUGAGGGUAGAGUGGCUAG 2381 CAUGAUGAGGGUAGAGUGGC 2382 GCAUGAUGAGGGUAGAGUGG 2383 GGGCAUGAUGAGGGUAGAGU 2384 GGUAGUUGAGAAGAAAAGUC 2385 CCAAACUCCGAGCUUAUAUU 2386 UCCAAACUCCGAGCUUAUAU 2387 GUCCAAACUCCGAGCUUAUA 2388 CGUCCAAACUCCGAGCUUAU 2389 CCGUCCAAACUCCGAGCUUA 2390 UCCGUCCAAACUCCGAGCUU 2391 CUCCGUCCAAACUCCGAGCU 2392 ACCCUCCGUCCAAACUCCGA 2393 AGACCCUCCGUCCAAACUCC 2394 CAGACCCUCCGUCCAAACUC 2395 UCCAGACCCUCCGUCCAAAC 2396 GUCCAGACCCUCCGUCCAAA 2397 AGACACGGAAAGGUCGCUGG 2398 CAGACACGGAAAGGUCGCUG 2399 ACAGACACGGAAAGGUCGCU 2400 CACAGACACGGAAAGGUCGC 2401 UCACAGACACGGAAAGGUCG 2402 AUCACAGACACGGAAAGGUC 2403 GAUCACAGACACGGAAAGGU 2404 UUGGCCUACUUACUUUGGCU 2405 CUUGGCCUACUUACUUUGGC 2406 ACUUGGCCUACUUACUUUGG 2407 GAGGAACUUGGCCUACUUAC 2408 CGAGGAACUUGGCCUACUUA 2409 CCGAGGAACUUGGCCUACUU 2410 ACCGAGGAACUUGGCCUACU 2411 AACCGAGGAACUUGGCCUAC 2412 GAACCGAGGAACUUGGCCUA 2413 GGAACCGAGGAACUUGGCCU 2414 AGGAACCGAGGAACUUGGCC 2415 UAGGAACCGAGGAACUUGGC 2416 AUAGGAACCGAGGAACUUGG 2417 UAUAGGAACCGAGGAACUUG 2418 AUCACAAGUUGCCACUGUUG 2419 CAUCACAAGUUGCCACUGUU 2420 AUCAUCACAAGUUGCCACUG 2421 CAUCAUCACAAGUUGCCACU 2422 CUGCUCCAUCAUCACAAGUU 2423 UCUGCUCCAUCAUCACAAGU 2424 CCCUCUGCUCCAUCAUCACA 2425 UCAGCCCUCUGCUCCAUCAU 2426 UGACUUCAGCCCUCUGCUCC 2427 GUGACUUCAGCCCUCUGCUC 2428 UGUGACUUCAGCCCUCUGCU 2429 GUGUGACUUCAGCCCUCUGC 2430 UGUGUGACUUCAGCCCUCUG 2431 GCCCACUCCGCUGCUUUUAG 2432 GGCCCACUCCGCUGCUUUUA 2433 AGGCCCACUCCGCUGCUUUU 2434 UAGGCCCACUCCGCUGCUUU 2435 UUAGGCCCACUCCGCUGCUU 2436 AUUAGGCCCACUCCGCUGCU 2437 UCAUUAGGCCCACUCCGCUG 2438 CUCAUUAGGCCCACUCCGCU 2439 AGCUCAUUAGGCCCACUCCG 2440 CUCCCAUAGAAAAGCUCACU 2441 GCUCCCAUAGAAAAGCUCAC 2442 UGCUCCCAUAGAAAAGCUCA 2443 CUGCUCCCAUAGAAAAGCUC 2444 CCUGCUCCCAUAGAAAAGCU 2445 UCCCUAUCUCCUGCUAACCC 2446 CCUCGAACUCUCCCUAUCUC 2447 CCCUCGAACUCUCCCUAUCU 2448 UCCCUCGAACUCUCCCUAUC 2449 GUCCCUCGAACUCUCCCUAU 2450 CUUUCCAUACUAGCUUCUGA 2451 CCUUUCCAUACUAGCUUCUG 2452 ACCUUUCCAUACUAGCUUCU 2453 CACACAAAUCACCUUUCCAU 2454 GUCACACAAAUCACCUUUCC 2455 UGUCACACAAAUCACCUUUC 2456 UUUGACAGGCAGGAAGUGGC 2457 GGUUUGACAGGCAGGAAGUG 2458 AGGUUUGACAGGCAGGAAGU 2459 AAGGUUUGACAGGCAGGAAG 2460 AACUUCCCAAGGUUUGACAG 2461 CAACUUCCCAAGGUUUGACA 2462 GAACAACUUCCCAAGGUUUG 2463 UGAACAACUUCCCAAGGUUU 2464 GUAGGUUGAACAACUUCCCA 2465 GGUAGGUUGAACAACUUCCC 2466 UGGUAGGUUGAACAACUUCC 2467 GGUUUUGGUAGGUUGAACAA 2468 UGAGGUUUUGGUAGGUUGAA 2469 CUGAGGUUUUGGUAGGUUGA 2470 CCUACAUUAUCCUCUUACUC 2471 GGACUUUACCUACAUUAUCC 2472 GUAUGAGGACUUUACCUACA 2473 GCCAGGUAUGAGGACUUUAC 2474 UGCCAGGUAUGAGGACUUUA 2475 GUGCCAGGUAUGAGGACUUU 2476 CUGUGCCAGGUAUGAGGACU 2477 UCUGUGCCAGGUAUGAGGAC 2478 CCUCAAGAGUUCUCCAGAAG 2479 CCCUCAAGAGUUCUCCAGAA 2480 ACCCUCAAGAGUUCUCCAGA 2481 ACACCCUCAAGAGUUCUCCA 2482 CACACCCUCAAGAGUUCUCC 2483 CCACACCCUCAAGAGUUCUC 2484 CCCACACCCUCAAGAGUUCU 2485 UUCCCACACCCUCAAGAGUU 2486 CAAUGCUGCACCUCACUUCC 2487 UACAAUGCUGCACCUCACUU 2488 CUACAAUGCUGCACCUCACU 2489 UCUACAAUGCUGCACCUCAC 2490 AUCUACAAUGCUGCACCUCA 2491 UAUCUACAAUGCUGCACCUC 2492 CUUAUCUACAAUGCUGCACC 2493 GUCUUAUCUACAAUGCUGCA 2494 UGUCUUAUCUACAAUGCUGC 2495 CUGUCUUAUCUACAAUGCUG 2496 CACCCUUCUGUCUUAUCUAC 2497 UCCACCCUUCUGUCUUAUCU 2498 GUCCACCCUUCUGUCUUAUC 2499 AGUCCACCCUUCUGUCUUAU 2500 AAGUCCACCCUUCUGUCUUA 2501 GAAAGCAAGCCAGGUUCUCA 2502 GGAAAGCAAGCCAGGUUCUC 2503 GGAAUUGGAAAGCAAGCCAG 2504 ACCAUGUCAUUGGCAUCUCC 2505 UACCAUGUCAUUGGCAUCUC 2506 CCUACCAUGUCAUUGGCAUC 2507 UCCUACCAUGUCAUUGGCAU 2508 CUCCUACCAUGUCAUUGGCA 2509 GCUCCUACCAUGUCAUUGGC 2510 UGCUCCUACCAUGUCAUUGG 2511 UCUUUGCUCCUACCAUGUCA 2512 CCUCUUUGCUCCUACCAUGU 2513 UUCCUCUUUGCUCCUACCAU 2514 UCUCCGUGUUCUUCAGUUUU 2515 CUCUCCGUGUUCUUCAGUUU 2516 AGCUCUCCGUGUUCUUCAGU 2517 UGCAGCUCUCCGUGUUCUUC 2518 GGUUGCAGCUCUCCGUGUUC 2519 AGGUUGCAGCUCUCCGUGUU 2520 AAAGGUUGCAGCUCUCCGUG 2521 UAAAGGUUGCAGCUCUCCGU 2522 CUAAAGGUUGCAGCUCUCCG 2523 CCUAAAGGUUGCAGCUCUCC 2524 UCCUAAAGGUUGCAGCUCUC 2525 CUCCUAAAGGUUGCAGCUCU 2526 CCUCCUAAAGGUUGCAGCUC 2527 GCACUUUGAUACCUCCUAAA 2528 GGCACUUUGAUACCUCCUAA 2529 GAUGUCCCACUUUGACUUUC 2530 UCGAUGUCCCACUUUGACUU 2531 GUCGAUGUCCCACUUUGACU 2532 GGUCGAUGUCCCACUUUGAC 2533 UGGUCGAUGUCCCACUUUGA 2534 UUGGUCGAUGUCCCACUUUG 2535 AUUGGUCGAUGUCCCACUUU 2536 CAUUGGUCGAUGUCCCACUU 2537 AACAUCCAUCAGUUGGCUCU 2538 CUGCCCAACAUCCAUCAGUU 2539 AGCUGCCCAACAUCCAUCAG 2540 UAGCUGCCCAACAUCCAUCA 2541 UUAGCUGCCCAACAUCCAUC 2542 UUUAGCUGCCCAACAUCCAU 2543 CUUUAGCUGCCCAACAUCCA 2544 CCUCUUUAGCUGCCCAACAU 2545 CCCUCUUUAGCUGCCCAACA 2546 UCCCUCUUUAGCUGCCCAAC 2547 UUCCCUCUUUAGCUGCCCAA 2548 CCUUCCCUCUUUAGCUGCCC 2549 CCCUUCCCUCUUUAGCUGCC 2550 GCAGGUCUUAUCCCAUGCCC 2551 GGGCAGGUCUUAUCCCAUGC 2552 AGGGCAGGUCUUAUCCCAUG 2553 AAGGGCAGGUCUUAUCCCAU 2554 GAAGGGCAGGUCUUAUCCCA 2555 AGAAGGGCAGGUCUUAUCCC 2556 CCAAUGGCAAGAAGCAAGAA 2557 CCCAAUGGCAAGAAGCAAGA 2558 GCCCAAUGGCAAGAAGCAAG 2559 UCCAAUGCCUGCCCAAUGGC 2560 CUCCAAUGCCUGCCCAAUGG 2561 UCUCCAAUGCCUGCCCAAUG 2562 GGUCUCCAAUGCCUGCCCAA 2563 UAGGGUCUCCAAUGCCUGCC 2564 GUAGGGUCUCCAAUGCCUGC 2565 AGUAGGGUCUCCAAUGCCUG 2566 CAGUAGGGUCUCCAAUGCCU 2567 GCAGUAGGGUCUCCAAUGCC 2568 AGCAGUAGGGUCUCCAAUGC 2569 CAGCAGUAGGGUCUCCAAUG 2570 UCAGCAGUAGGGUCUCCAAU 2571 AUUCAGCAGUAGGGUCUCCA 2572 CAUUCAGCAGUAGGGUCUCC 2573 CCAUUCAGCAGUAGGGUCUC 2574 UCCAUUCAGCAGUAGGGUCU 2575 ACUCCAUUCAGCAGUAGGGU 2576 CACUCCAUUCAGCAGUAGGG 2577 GCACUCCAUUCAGCAGUAGG 2578 AGCACUCCAUUCAGCAGUAG 2579 UAGCACUCCAUUCAGCAGUA 2580 GGUUAGCACUCCAUUCAGCA 2581 GGUUAGCACUCCAUUCAGCA 2582 GGGUUAGCACUCCAUUCAGC 2583 CAGGGUUAGCACUCCAUUCA 2584 CCAGGGUUAGCACUCCAUUC 2585 ACCAGGGUUAGCACUCCAUU 2586 CACCAGGGUUAGCACUCCAU 2587 GCACCAGGGUUAGCACUCCA 2588 AGCACCAGGGUUAGCACUCC 2589 UAGCACCAGGGUUAGCACUC 2590 CUAGCACCAGGGUUAGCACU 2591 UCUAGCACCAGGGUUAGCAC 2592 CUCUAGCACCAGGGUUAGCA 2593 CCUCUAGCACCAGGGUUAGC 2594 UCCUCUAGCACCAGGGUUAG 2595 CUCCUCUAGCACCAGGGUUA 2596 CCUCCUCUAGCACCAGGGUU 2597 UCCUCCUCUAGCACCAGGGU 2598 GUUCCAUCCUCCUCUAGCAC 2599 AAGUCCUCACUGUCCACUGC 2600 GAAGUCCUCACUGUCCACUG 2601 AGAAGUCCUCACUGUCCACU 2602 AAGAAGUCCUCACUGUCCAC 2603 GAAGAAGUCCUCACUGUCCA 2604 GGAAGAAGUCCUCACUGUCC 2605 UGGAAGAAGUCCUCACUGUC 2606 CUGGAAGAAGUCCUCACUGU 2607 AGCUGGAAGAAGUCCUCACU 2608 ACUGCAACACCAUCAGGCAC 2609 GACUGCAACACCAUCAGGCA 2610 AGACUGCAACACCAUCAGGC 2611 CAGACUGCAACACCAUCAGG 2612 CCAGACUGCAACACCAUCAG 2613 GACCAGACUGCAACACCAUC 2614 CUCUGACCAGACUGCAACAC 2615 AGCUCUGACCAGACUGCAAC 2616 CCAGCUCUGACCAGACUGCA 2617 UGUAGGGCUCCAGCUCUGAC 2618 CUUGUAGGGCUCCAGCUCUG 2619 CCUUGUAGGGCUCCAGCUCU 2620 ACAGGCAUUGGAAGCAGCCC 2621 GACAGGCAUUGGAAGCAGCC 2622 AAGGACAGGCAUUGGAAGCA 2623 AAAGGACAGGCAUUGGAAGC 2624 UAAAGGACAGGCAUUGGAAG 2625 CUAAAGGACAGGCAUUGGAA 2626 GCUCUAAAGGACAGGCAUUG 2627 AGCUCUAAAGGACAGGCAUU 2628 AAGCUCUAAAGGACAGGCAU 2629 AAAGCUCUAAAGGACAGGCA 2630 GAAAGCUCUAAAGGACAGGC 2631 CGGGAAAGCUCUAAAGGACA 2632 CCGGGAAAGCUCUAAAGGAC 2633 AGGGUUAAGCUAGAGAGGAA 2634 UCAGGGUUAAGCUAGAGAGG 2635 GAUCAGGGUUAAGCUAGAGA 2636 GGAUCAGGGUUAAGCUAGAG 2637 AGGAUCAGGGUUAAGCUAGA 2638 CCCAGGAUCAGGGUUAAGCU 2639 CAACUCCUCCUGCACCUGGU 2640 ACAACUCCUCCUGCACCUGG 2641 GACAAUUCCACAACUCCUCC 2642 UGACAAUUCCACAACUCCUC 2643 UUGACAAUUCCACAACUCCU 2644 CUUGACAAUUCCACAACUCC 2645 UCCUUGACAAUUCCACAACU 2646 AUCCUUGACAAUUCCACAAC 2647 CAUCCUUGACAAUUCCACAA 2648 ACAUCCUUGACAAUUCCACA 2649 GACAUCCUUGACAAUUCCAC 2650 UGACAUCCUUGACAAUUCCA 2651 UGUGUGACAUCCUUGACAAU 2652 ACUGUGUGACAUCCUUGACA 2653 ACUUUCUGUCCACUGUGUGA 2654 CCUCGCUUGGACUUUCUGUC 2655 CCCUCGCUUGGACUUUCUGU 2656 UCCCUCGCUUGGACUUUCUG 2657 CUCCCUCGCUUGGACUUUCU 2658 CCUCCCUCGCUUGGACUUUC 2659 CCCUCCCUCGCUUGGACUUU 2660 UCCAUCAGCACUGGGUCAGA 2661 ACCACUAAUCUCCAUCAGCA 2662 CACCACUAAUCUCCAUCAGC 2663 CCACCACUAAUCUCCAUCAG 2664 CCCACCACUAAUCUCCAUCA 2665 ACCAGACACCCACCACUAAU 2666 UACCAGACACCCACCACUAA 2667 CUCAUACCAGACACCCACCA 2668 CCUCAUACCAGACACCCACC 2669 UCCUCAUACCAGACACCCAC 2670 AUCCUCAUACCAGACACCCA 2671 GAUCCUCAUACCAGACACCC 2672 AGAUCCUCAUACCAGACACC 2673 UAGAUCCUCAUACCAGACAC 2674 GUAGAUCCUCAUACCAGACA 2675 AGUAGAUCCUCAUACCAGAC 2676 CAGUAGAUCCUCAUACCAGA 2677 UGCAGUAGAUCCUCAUACCA 2678 GUGCAGUAGAUCCUCAUACC 2679 AGUGCAGUAGAUCCUCAUAC 2680 ACUCUGUAGGACACCCUUGU 2681 CACUCUGUAGGACACCCUUG 2682 CCACUCUGUAGGACACCCUU 2683 UCCACUCUGUAGGACACCCU 2684 CUCCACUCUGUAGGACACCC 2685 ACUCCACUCUGUAGGACACC 2686 CACUCCACUCUGUAGGACAC 2687 AGCACUCCACUCUGUAGGAC 2688 UAUGACAGCACUCCACUCUG 2689 AUAUGACAGCACUCCACUCU 2690 UUGCUGUGCUUGGGCCUCUC 2691 ACGUCAAAGGUGAAUCGGGC 2692 CACGUCAAAGGUGAAUCGGG 2693 ACACGUCAAAGGUGAAUCGG 2694 UACACGUCAAAGGUGAAUCG 2695 GUACACGUCAAAGGUGAAUC 2696 GGCUGCCAAAGAGGUCUCGA 2697 UCAGGCUGCCAAAGAGGUCU 2698 CAUUCAGGCUGCCAAAGAGG 2699 GACAUUCAGGCUGCCAAAGA 2700 UGACAUUCAGGCUGCCAAAG 2701 CUUUGACAUUCAGGCUGCCA 2702 GCUUUGACAUUCAGGCUGCC 2703 CCGUAGAAUGUGGCUUUGAC 2704 GCCCGUAGAAUGUGGCUUUG 2705 UAGAGCCCGUAGAAUGUGGC 2706 GUAGAGCCCGUAGAAUGUGG 2707 AGUAGAGCCCGUAGAAUGUG 2708 AGAGUAGAGCCCGUAGAAUG 2709 UAGAGUAGAGCCCGUAGAAU 2710 AUAGAGUAGAGCCCGUAGAA 2711 CAUAGAGUAGAGCCCGUAGA 2712 UCAUAGAGUAGAGCCCGUAG 2713 CUCAUAGAGUAGAGCCCGUA 2714 GAAAGUCACAACUCAUAGAG 2715 CCUUGAAAGUCACAACUCAU 2716 AAGUCCUUGAAAGUCACAAC 2717 CCAAGUCCUUGAAAGUCACA 2718 UUCUUUGGGCCAAGUCCUUG 2719 UUUCUUUGGGCCAAGUCCUU 2720 UUGAUUUCUGACCUGAGUAC 2721 GUUGAUUUCUGACCUGAGUA 2722 GGGACUAUCCAACUGUAGGG 2723 GCAAGAGGACGAAUUAUGGG 2724 UGCAAGAGGACGAAUUAUGG 2725 GUGCAAGAGGACGAAUUAUG 2726 GGUGCAAGAGGACGAAUUAU 2727 GGGUGCAAGAGGACGAAUUA 2728 UGGGUGCAAGAGGACGAAUU 2729 GUGGGUGCAAGAGGACGAAU 2730 GGUGGGUGCAAGAGGACGAA 2731 UAGGUGGGUGCAAGAGGACG 2732 GUAGGUGGGUGCAAGAGGAC 2733 GGUAGGUGGGUGCAAGAGGA 2734 CCACAAGCAAGAGCUAACUA 2735 ACUUUCCACAAGCAAGAGCU 2736 GACUUUCCACAAGCAAGAGC 2737 GGACUUUCCACAAGCAAGAG 2738 AGGACUUUCCACAAGCAAGA 2739 GAGGACUUUCCACAAGCAAG 2740 UGAGGACUUUCCACAAGCAA 2741 AUGAGGACUUUCCACAAGCA 2742 GAUGAGGACUUUCCACAAGC 2743 AGAUGAGGACUUUCCACAAG 2744 GAGAUGAGGACUUUCCACAA 2745 GGAGAUGAGGACUUUCCACA 2746 UGGGAGAUGAGGACUUUCCA 2747 GCUGGGAGAUGAGGACUUUC 2748 UCAAGCUGGGAGAUGAGGAC 2749 AAGCCAUCAAGCUGGGAGAU 2750 GAAGCCAUCAAGCUGGGAGA 2751 GGAGGAAGCCAUCAAGCUGG 2752 GGGAGGAAGCCAUCAAGCUG 2753 AACUUGGGAGGAAGCCAUCA 2754 AAACUUGGGAGGAAGCCAUC 2755 CAGCAGUGUGGAGGUCCAAC 2756 GCAGCAGUGUGGAGGUCCAA 2757 UGCAGCAGUGUGGAGGUCCA 2758 UUGCAGCAGUGUGGAGGUCC 2759 GGUGGAGGAAAUUCCCAGCA 2760 ACGAAGGGUGGAGGAAAUUC 2761 GACGAAGGGUGGAGGAAAUU 2762 AUGACGAAGGGUGGAGGAAA 2763 CAUGACGAAGGGUGGAGGAA 2764 GCAUGACGAAGGGUGGAGGA 2765 UGCAUGACGAAGGGUGGAGG 2766 CUGCAUGACGAAGGGUGGAG 2767 ACUGCAUGACGAAGGGUGGA 2768 CACUGCAUGACGAAGGGUGG 2769 CCACUGCAUGACGAAGGGUG 2770 UCCACUGCAUGACGAAGGGU 2771 CUCCACUGCAUGACGAAGGG 2772 CCUCCACUGCAUGACGAAGG 2773 CCCUCCACUGCAUGACGAAG 2774 CUUAGUAGGAAUGGAGGCGG 2775 CCUUAGUAGGAAUGGAGGCG 2776 CCCUUAGUAGGAAUGGAGGC 2777 UCGGUUGGAAUGAUUCUGGG 2778 GUCGGUUGGAAUGAUUCUGG 2779 GGUCGGUUGGAAUGAUUCUG 2780 GGGUCGGUUGGAAUGAUUCU 2781 UGGGUCGGUUGGAAUGAUUC 2782 GUGGGUCGGUUGGAAUGAUU 2783 AGUGGGUCGGUUGGAAUGAU 2784 CAGUGGGUCGGUUGGAAUGA 2785 GCAGUGGGUCGGUUGGAAUG 2786 UGCAGUGGGUCGGUUGGAAU 2787 UUGCAGUGGGUCGGUUGGAA 2788 UUUGCAGUGGGUCGGUUGGA 2789 CUUUGCAGUGGGUCGGUUGG 2790 UCUUUGCAGUGGGUCGGUUG 2791 UAGUCUUUGCAGUGGGUCGG 2792 AUAGUCUUUGCAGUGGGUCG 2793 CUGUCAUAGUCUUUGCAGUG 2794 UGCUGUCAUAGUCUUUGCAG 2795 UCUAGCCUGUACUGUCUGCA 2796 AUCUAGCCUGUACUGUCUGC 2797 UAUCUAGCCUGUACUGUCUG 2798 UUAUCUAGCCUGUACUGUCU 2799 GUUAUCUAGCCUGUACUGUC 2800 GGUUAUCUAGCCUGUACUGU 2801 GGGUUAUCUAGCCUGUACUG 2802 UGGGUUAUCUAGCCUGUACU 2803 GUGGGUUAUCUAGCCUGUAC 2804 GGUGGGUUAUCUAGCCUGUA 2805 GGGUGGGUUAUCUAGCCUGU 2806 UGGGUGGGUUAUCUAGCCUG 2807 UUGGGUGGGUUAUCUAGCCU 2808 AUUGGGUGGGUUAUCUAGCC 2809 AAUUGGGUGGGUUAUCUAGC 2810 AAAUUGGGUGGGUUAUCUAG 2811 GGAAAUUGGGUGGGUUAUCU 2812 GGGAAAUUGGGUGGGUUAUC 2813 GAAAGGUUCUGUCACGAGGG 2814 GCUGAAAGGUUCUGUCACGA 2815 UGCUGAAAGGUUCUGUCACG 2816 GGCGUUAUGCUGAAAGGUUC 2817 AGGCGUUAUGCUGAAAGGUU 2818 GAGGCGUUAUGCUGAAAGGU 2819 UGAGGCGUUAUGCUGAAAGG 2820 GUGAGGCGUUAUGCUGAAAG 2821 AUGUGAGGCGUUAUGCUGAA 2822 GAUGUGAGGCGUUAUGCUGA 2823 GGAUGUGAGGCGUUAUGCUG 2824 GGGAUGUGAGGCGUUAUGCU 2825 CUUGGGAUGUGAGGCGUUAU 2826 AGACUUGGGAUGUGAGGCGU 2827 UAGACUUGGGAUGUGAGGCG 2828 AUAGACUUGGGAUGUGAGGC 2829 UAUAGACUUGGGAUGUGAGG 2830 GGGUAUAGACUUGGGAUGUG 2831 AGGGUAUAGACUUGGGAUGU 2832 AAGGUGGCUAGGAAAGAACA 2833 AAAGGUGGCUAGGAAAGAAC 2834 GAAAGGUGGCUAGGAAAGAA 2835 ACAUCUUGAUCUUGGCCUUU 2836 GGCUGGGAUCAAGAUGCCUG 2837 GUCAGGCUGGGAUCAAGAUG 2838 AGUCAGGCUGGGAUCAAGAU 2839 CAGUCAGGCUGGGAUCAAGA 2840 AGCAGUCAGGCUGGGAUCAA 2841 GAUGUAGCAGCAGUCAGGCU 2842 GGAUUAGAUGUAGCAGCAGU 2843 GGGAUUAGAUGUAGCAGCAG 2844 GACAGGAGGCAUUGGUAGGG 2845 UUAGGGACAGGAGGCAUUGG 2846 UUUAGGGACAGGAGGCAUUG 2847 GAGUUUAGGGACAGGAGGCA 2848 GGAGUUUAGGGACAGGAGGC 2849 GCUGUCAUCAGUAUGCUGGG 2850 GGCUGUCAUCAGUAUGCUGG 2851 GGGCUGUCAUCAGUAUGCUG 2852 AGGGCUGUCAUCAGUAUGCU 2853 AGAGAGGGCUGUCAUCAGUA 2854 CAGAGAGGGCUGUCAUCAGU 2855 UCAGAGAGGGCUGUCAUCAG 2856 GUCAGAGAGGGCUGUCAUCA 2857 GGUAAAGUCAGAGAGGGCUG 2858 GGGAAGGGUAUGAAGACAGA 2859 GUCAGAAGUCUUAGUGGUAA 2860 AGUCAGAAGUCUUAGUGGUA 2861 GAGUCAGAAGUCUUAGUGGU 2862 CUGGGACUGGGUGUUGAUGG 2863 AUCUGGGACUGGGUGUUGAU 2864 GAUCUGGGACUGGGUGUUGA 2865 UGGAUCUGGGACUGGGUGUU 2866 UUUGGAUCUGGGACUGGGUG 2867 GCUUUGGAUCUGGGACUGGG 2868

In some embodiments, the antisense nucleic acid molecules targeted to Transcript D comprise or consist of the nucleotide sequences shown in Table 5.

TABLE 5 SEQ ID Sequence NO: ACACUGCUGAGCUGGAAGAC 2869 CGAGACACUGCUGAGCUGGA 2870 ACGAGACACUGCUGAGCUGG 2871 AACGAGACACUGCUGAGCUG 2872 GAACGAGACACUGCUGAGCU 2873 GGAACGAGACACUGCUGAGC 2874 GGGAACGAGACACUGCUGAG 2875 AGGGAACGAGACACUGCUGA 2876 CAGGGAACGAGACACUGCUG 2877 CCAGGGAACGAGACACUGCU 2878 AAGGAUGUCGGUCUGCUACC 2879 GAAGGAUGUCGGUCUGCUAC 2880 AGAAGGAUGUCGGUCUGCUA 2881 UAGGCCCAGAAGGAUGUCGG 2882 GUAGGCCCAGAAGGAUGUCG 2883 UGUAGGCCCAGAAGGAUGUC 2884 CUGUAGGCCCAGAAGGAUGU 2885 CCUGUAGGCCCAGAAGGAUG 2886 ACCUGUAGGCCCAGAAGGAU 2887 CUUCUCAUCGGGCAUCACAG 2888 CCUUCUCAUCGGGCAUCACA 2889 ACCUUCUCAUCGGGCAUCAC 2890 CACCUUCUCAUCGGGCAUCA 2891 GCACCUUCUCAUCGGGCAUC 2892 GGCACCUUCUCAUCGGGCAU 2893 UGGCACCUUCUCAUCGGGCA 2894 AUGGCACCUUCUCAUCGGGC 2895 CAUGGCACCUUCUCAUCGGG 2896 GCAUGGCACCUUCUCAUCGG 2897 GGCAUGGCACCUUCUCAUCG 2898 GAGGCAUGGCACCUUCUCAU 2899 GGAGGCAUGGCACCUUCUCA 2900 GACUCCCAGGCAGAAAAGAG 2901 GGACUCCCAGGCAGAAAAGA 2902 AGGACUCCCAGGCAGAAAAG 2903 UCAGGACUCCCAGGCAGAAA 2904 GAAGUCAGGACUCCCAGGCA 2905 GUGGAAGUCAGGACUCCCAG 2906 UCGUGGAAGUCAGGACUCCC 2907 CUCGUGGAAGUCAGGACUCC 2908 CCUCGUGGAAGUCAGGACUC 2909 UGGGUCCUCGUGGAAGUCAG 2910 CUGGGUCCUCGUGGAAGUCA 2911 UCUGGGUCCUCGUGGAAGUC 2912 GUCUGGGUCCUCGUGGAAGU 2913 AAGAAGGAGUUGUGUUUGAG 2914 CCAAGAAGGAGUUGUGUUUG 2915 GUUCCAAGAAGGAGUUGUGU 2916 GGUUCCAAGAAGGAGUUGUG 2917 CAGGUCAACUGACUGGGAGC 2918 UGCCUGUUUACCACUGAGCU 2919 AUGCCUGUUUACCACUGAGC 2920 UAUGCCUGUUUACCACUGAG 2921 UUAUGCCUGUUUACCACUGA 2922 UUUAUGCCUGUUUACCACUG 2923 CUUUAUGCCUGUUUACCACU 2924 ACUUUAUGCCUGUUUACCAC 2925 UAGAGAUAGUGACAGCCUGG 2926 GUAGAGAUAGUGACAGCCUG 2927 UGGUGGUAGAGAUAGUGACA 2928 GUGGUGGUAGAGAUAGUGAC 2929 UAGAGGAGUGGUGGUAGAGA 2930 ACUAGAGGAGUGGUGGUAGA 2931 AGACUAGAGGAGUGGUGGUA 2932 CAGACUAGAGGAGUGGUGGU 2933 CCAGACUAGAGGAGUGGUGG 2934 GCCAGACUAGAGGAGUGGUG 2935 GGCCAGACUAGAGGAGUGGU 2936 GCCCAGAUGUGCUAGAAUGG 2937 UGCCCAGAUGUGCUAGAAUG 2938 UUGCCCAGAUGUGCUAGAAU 2939 UUUGCCCAGAUGUGCUAGAA 2940 UUUUGCCCAGAUGUGCUAGA 2941 CCAGUUUUGCCCAGAUGUGC 2942 AUCCAGUUUUGCCCAGAUGU 2943 CCAUCCAGUUUUGCCCAGAU 2944 CACCAUCCAGUUUUGCCCAG 2945 CCACCAUCCAGUUUUGCCCA 2946 CCCACCAUCCAGUUUUGCCC 2947 UUGCUCCCAGCUUGGUAAGU 2948 GCUUGCUCCCAGCUUGGUAA 2949 AUCCUGCUUGCUCCCAGCUU 2950 AAUCCUGCUUGCUCCCAGCU 2951 CAAUCCUGCUUGCUCCCAGC 2952 CCAAUCCUGCUUGCUCCCAG 2953 AACCUUUCAGCUUCUCCAGG 2954 UAACCUUUCAGCUUCUCCAG 2955 UUAACCUUUCAGCUUCUCCA 2956 ACUGCUGCUUAACCUUUCAG 2957 UACUGCUGCUUAACCUUUCA 2958 CUACUGCUGCUUAACCUUUC 2959 CCUACUGCUGCUUAACCUUU 2960 GCCUACUGCUGCUUAACCUU 2961 CAGGACAGGAGUAGGCACCU 2962 ACAGGACAGGAGUAGGCACC 2963 GCACAGGACAGGAGUAGGCA 2964 AUAGGCACAGGACAGGAGUA 2965 GAUAGGCACAGGACAGGAGU 2966 UGAUAGGCACAGGACAGGAG 2967 ACCCUCUGCAAAUGUGAUAG 2968 CUUACCCUCUGCAAAUGUGA 2969 GUCUUACCCUCUGCAAAUGU 2970 UGUCUUACCCUCUGCAAAUG 2971 UUGUCUUACCCUCUGCAAAU 2972 CUUGUCUUACCCUCUGCAAA 2973 UCUUGUCUUACCCUCUGCAA 2974 CAUUCUUGUCUUACCCUCUG 2975 CCCAUUCUUGUCUUACCCUC 2976 GAGCCUCAUCUUGUCCCUCC 2977 UGAGCCUCAUCUUGUCCCUC 2978

In some embodiments, the antisense nucleic acid molecules targeted to Transcript E comprise or consist of the nucleotide sequences shown in Table 6.

TABLE 6 Sequence SEQ ID NO: ACCACGCAGUCAACCUUCUG 2979 UACCACGCAGUCAACCUUCU 2980 CUACCACGCAGUCAACCUUC 2981 CCUACCACGCAGUCAACCUU 2982 CCCUACCACGCAGUCAACCU 2983 UUGCCUUCGGCUUGCUCUGG 2984 CUUGCCUUCGGCUUGCUCUG 2985 GCUUGCCUUCGGCUUGCUCU 2986 UGCUUGCCUUCGGCUUGCUC 2987 GUGCUUGCCUUCGGCUUGCU 2988 UCGUGCUUGCCUUCGGCUUG 2989 AUCGUGCUUGCCUUCGGCUU 2990 CAUCGUGCUUGCCUUCGGCU 2991 AGCGCCAUCGUGCUUGCCUU 2992 UGGUGAGCGCCAUCGUGCUU 2993 CUGAUGCUCGGCUGCUACAG 2994 GCUGAUGCUCGGCUGCUACA 2995 UUUCGGGCUGAUGCUCGGCU 2996 UCCUUUCGGGCUGAUGCUCG 2997 UUCCUUUCGGGCUGAUGCUC 2998 CUUCCUUUCGGGCUGAUGCU 2999 GCUUCCUUUCGGGCUGAUGC 3000 UGCUUCCUUUCGGGCUGAUG 3001 GUGCUUCCUUUCGGGCUGAU 3002 CGUGCUUCCUUUCGGGCUGA 3003 UCGUGCUUCCUUUCGGGCUG 3004 UUCGUGCUUCCUUUCGGGCU 3005 UUUCGUGCUUCCUUUCGGGC 3006 CUUUCGUGCUUCCUUUCGGG 3007 GCUUUCGUGCUUCCUUUCGG 3008 AUGUACGCCAGCGUGCUGCU 3009 UCAGCAUGUACGCCAGCGUG 3010 AGGCGGUGUACUACGUGUGC 3011 AAGGCGGUGUACUACGUGUG 3012 CAAGGCGGUGUACUACGUGU 3013 GCAAGGCGGUGUACUACGUG 3014 UGCAAGGCGGUGUACUACGU 3015 CUGCAAGGCGGUGUACUACG 3016 GCUGCAAGGCGGUGUACUAC 3017 GGCUGCAAGGCGGUGUACUA 3018 GCUCUUUGUGGCCUUCCUGA 3019 CGCUCUUUGUGGCCUUCCUG 3020

In some embodiments, the antisense nucleic acid molecules targeted to Transcript F comprise or consist of the nucleotide sequences shown in Table 7.

TABLE 7 Sequence SEQ ID NO: AGAAGUCCUCACUGUCCACU 3021 AAGAAGUCCUCACUGUCCAC 3022 GAAGAAGUCCUCACUGUCCA 3023 GGAAGAAGUCCUCACUGUCC 3024 UGGAAGAAGUCCUCACUGUC 3025 CUGGAAGAAGUCCUCACUGU 3026 AGCUGGAAGAAGUCCUCACU 3027 ACUGCAACACCAUCAGGCAC 3028 GACUGCAACACCAUCAGGCA 3029 AGACUGCAACACCAUCAGGC 3030 CAGACUGCAACACCAUCAGG 3031 CCAGACUGCAACACCAUCAG 3032 GACCAGACUGCAACACCAUC 3033 CUCUGACCAGACUGCAACAC 3034 AGCUCUGACCAGACUGCAAC 3035 CCAGCUCUGACCAGACUGCA 3036 UGUAGGGCUCCAGCUCUGAC 3037 CUUGUAGGGCUCCAGCUCUG 3038 CCUUGUAGGGCUCCAGCUCU 3039 ACAGGCAUUGGAAGCAGCCC 3040 GACAGGCAUUGGAAGCAGCC 3041 AAGGACAGGCAUUGGAAGCA 3042 AAAGGACAGGCAUUGGAAGC 3043 UAAAGGACAGGCAUUGGAAG 3044 CUAAAGGACAGGCAUUGGAA 3045 GCUCUAAAGGACAGGCAUUG 3046 AGCUCUAAAGGACAGGCAUU 3047 AAGCUCUAAAGGACAGGCAU 3048 AAAGCUCUAAAGGACAGGCA 3049 GAAAGCUCUAAAGGACAGGC 3050 CGGGAAAGCUCUAAAGGACA 3051 CCGGGAAAGCUCUAAAGGAC 3052 AGGGUUAAGCUAGAGAGGAA 3053 UCAGGGUUAAGCUAGAGAGG 3054 GAUCAGGGUUAAGCUAGAGA 3055 GGAUCAGGGUUAAGCUAGAG 3056 AGGAUCAGGGUUAAGCUAGA 3057 CCCAGGAUCAGGGUUAAGCU 3058 CAACUCCUCCUGCACCUGGU 3059 ACAACUCCUCCUGCACCUGG 3060 GACAAUUCCACAACUCCUCC 3061 UGACAAUUCCACAACUCCUC 3062 UUGACAAUUCCACAACUCCU 3063 CUUGACAAUUCCACAACUCC 3064 UCCUUGACAAUUCCACAACU 3065 AUCCUUGACAAUUCCACAAC 3066 CAUCCUUGACAAUUCCACAA 3067 ACAUCCUUGACAAUUCCACA 3068 GACAUCCUUGACAAUUCCAC 3069 UGACAUCCUUGACAAUUCCA 3070 UGUGUGACAUCCUUGACAAU 3071 ACUGUGUGACAUCCUUGACA 3072 ACUUUCUGUCCACUGUGUGA 3073 CCUCGCUUGGACUUUCUGUC 3074 CCCUCGCUUGGACUUUCUGU 3075 UCCCUCGCUUGGACUUUCUG 3076 CUCCCUCGCUUGGACUUUCU 3077 CCUCCCUCGCUUGGACUUUC 3078 CCCUCCCUCGCUUGGACUUU 3079 UCCAUCAGCACUGGGUCAGA 3080 ACCACUAAUCUCCAUCAGCA 3081 CACCACUAAUCUCCAUCAGC 3082 CCACCACUAAUCUCCAUCAG 3083 CCCACCACUAAUCUCCAUCA 3084 ACCAGACACCCACCACUAAU 3085 UACCAGACACCCACCACUAA 3086 CUCAUACCAGACACCCACCA 3087 CCUCAUACCAGACACCCACC 3088 UCCUCAUACCAGACACCCAC 3089 AUCCUCAUACCAGACACCCA 3090 GAUCCUCAUACCAGACACCC 3091 AGAUCCUCAUACCAGACACC 3092 UAGAUCCUCAUACCAGACAC 3093 GUAGAUCCUCAUACCAGACA 3094 AGUAGAUCCUCAUACCAGAC 3095 CAGUAGAUCCUCAUACCAGA 3096 UGCAGUAGAUCCUCAUACCA 3097 GUGCAGUAGAUCCUCAUACC 3098 AGUGCAGUAGAUCCUCAUAC 3099 ACUCUGUAGGACACCCUUGU 3100 CACUCUGUAGGACACCCUUG 3101 CCACUCUGUAGGACACCCUU 3102 UCCACUCUGUAGGACACCCU 3103 CUCCACUCUGUAGGACACCC 3104 ACUCCACUCUGUAGGACACC 3105 CACUCCACUCUGUAGGACAC 3106 AGCACUCCACUCUGUAGGAC 3107 UAUGACAGCACUCCACUCUG 3108 AUAUGACAGCACUCCACUCU 3109 UUGCUGUGCUUGGGCCUCUC 3110 ACGUCAAAGGUGAAUCGGGC 3111 CACGUCAAAGGUGAAUCGGG 3112 ACACGUCAAAGGUGAAUCGG 3113 UACACGUCAAAGGUGAAUCG 3114 GUACACGUCAAAGGUGAAUC 3115 GGCUGCCAAAGAGGUCUCGA 3116 UCAGGCUGCCAAAGAGGUCU 3117 CAUUCAGGCUGCCAAAGAGG 3118 GACAUUCAGGCUGCCAAAGA 3119 UGACAUUCAGGCUGCCAAAG 3120 CUUUGACAUUCAGGCUGCCA 3121 GCUUUGACAUUCAGGCUGCC 3122 CCGUAGAAUGUGGCUUUGAC 3123 GCCCGUAGAAUGUGGCUUUG 3124 UAGAGCCCGUAGAAUGUGGC 3125 GUAGAGCCCGUAGAAUGUGG 3126 AGUAGAGCCCGUAGAAUGUG 3127 AGAGUAGAGCCCGUAGAAUG 3128 UAGAGUAGAGCCCGUAGAAU 3129 AUAGAGUAGAGCCCGUAGAA 3130 CAUAGAGUAGAGCCCGUAGA 3131 UCAUAGAGUAGAGCCCGUAG 3132 CUCAUAGAGUAGAGCCCGUA 3133 GAAAGUCACAACUCAUAGAG 3134 CCUUGAAAGUCACAACUCAU 3135 AAGUCCUUGAAAGUCACAAC 3136 CCAAGUCCUUGAAAGUCACA 3137 UUCUUUGGGCCAAGUCCUUG 3138 UUUCUUUGGGCCAAGUCCUU 3139 UUGAUUUCUGACCUGAGUAC 3140 GUUGAUUUCUGACCUGAGUA 3141 GGGACUAUCCAACUGUAGGG 3142 GCAAGAGGACGAAUUAUGGG 3143 UGCAAGAGGACGAAUUAUGG 3144 GUGCAAGAGGACGAAUUAUG 3145 GGUGCAAGAGGACGAAUUAU 3146 GGGUGCAAGAGGACGAAUUA 3147 UGGGUGCAAGAGGACGAAUU 3148 GUGGGUGCAAGAGGACGAAU 3149 GGUGGGUGCAAGAGGACGAA 3150 UAGGUGGGUGCAAGAGGACG 3151 GUAGGUGGGUGCAAGAGGAC 3152 GGUAGGUGGGUGCAAGAGGA 3153 CCACAAGCAAGAGCUAACUA 3154 ACUUUCCACAAGCAAGAGCU 3155 GACUUUCCACAAGCAAGAGC 3156 GGACUUUCCACAAGCAAGAG 3157 AGGACUUUCCACAAGCAAGA 3158 GAGGACUUUCCACAAGCAAG 3159 UGAGGACUUUCCACAAGCAA 3160 AUGAGGACUUUCCACAAGCA 3161 GAUGAGGACUUUCCACAAGC 3162 AGAUGAGGACUUUCCACAAG 3163 GAGAUGAGGACUUUCCACAA 3164 GGAGAUGAGGACUUUCCACA 3165 UGGGAGAUGAGGACUUUCCA 3166 GCUGGGAGAUGAGGACUUUC 3167 UCAAGCUGGGAGAUGAGGAC 3168 AAGCCAUCAAGCUGGGAGAU 3169 GAAGCCAUCAAGCUGGGAGA 3170 GGAGGAAGCCAUCAAGCUGG 3171 GGGAGGAAGCCAUCAAGCUG 3172 AACUUGGGAGGAAGCCAUCA 3173 AAACUUGGGAGGAAGCCAUC 3174 CAGCAGUGUGGAGGUCCAAC 3175 GCAGCAGUGUGGAGGUCCAA 3176 UGCAGCAGUGUGGAGGUCCA 3177 UUGCAGCAGUGUGGAGGUCC 3178 GGUGGAGGAAAUUCCCAGCA 3179 ACGAAGGGUGGAGGAAAUUC 3180 GACGAAGGGUGGAGGAAAUU 3181 AUGACGAAGGGUGGAGGAAA 3182 CAUGACGAAGGGUGGAGGAA 3183 GCAUGACGAAGGGUGGAGGA 3184 UGCAUGACGAAGGGUGGAGG 3185 CUGCAUGACGAAGGGUGGAG 3186 ACUGCAUGACGAAGGGUGGA 3187 CACUGCAUGACGAAGGGUGG 3188 CCACUGCAUGACGAAGGGUG 3189 UCCACUGCAUGACGAAGGGU 3190 CUCCACUGCAUGACGAAGGG 3191 CCUCCACUGCAUGACGAAGG 3192 CCCUCCACUGCAUGACGAAG 3193 CUUAGUAGGAAUGGAGGCGG 3194 CCUUAGUAGGAAUGGAGGCG 3195 CCCUUAGUAGGAAUGGAGGC 3196

In some embodiments, the siRNA molecules targeted to Transcript A comprise or consist of the nucleotide sequences (sense and antisense strands) shown in Table 8.

TABLE 8 SEQ SEQ ID ID Sense Sequence NO: Antisense Sequence NO: GACCGCCUGCAGAAGGUUG 3197 CAACCUUCUGCAGGCGGUC 3198 ACCGCCUGCAGAAGGUUGA 3199 UCAACCUUCUGCAGGCGGU 3200 CCGCCUGCAGAAGGUUGAC 3201 GUCAACCUUCUGCAGGCGG 3202 CGCCUGCAGAAGGUUGACU 3203 AGUCAACCUUCUGCAGGCG 3204 GCCUGCAGAAGGUUGACUG 3205 CAGUCAACCUUCUGCAGGC 3206 CAGAAGGUUGACUGCGUGG 3207 CCACGCAGUCAACCUUCUG 3208 AGAAGGUUGACUGCGUGGU 3209 ACCACGCAGUCAACCUUCU 3210 GAAGGUUGACUGCGUGGUA 3211 UACCACGCAGUCAACCUUC 3212 AAGGUUGACUGCGUGGUAG 3213 CUACCACGCAGUCAACCUU 3214 AGGUUGACUGCGUGGUAGG 3215 CCUACCACGCAGUCAACCU 3216 GGUUGACUGCGUGGUAGGG 3217 CCCUACCACGCAGUCAACC 3218 CCAGAGCAAGCCGAAGGCA 3219 UGCCUUCGGCUUGCUCUGG 3220 CAGAGCAAGCCGAAGGCAA 3221 UUGCCUUCGGCUUGCUCUG 3222 AGAGCAAGCCGAAGGCAAG 3223 CUUGCCUUCGGCUUGCUCU 3224 GAGCAAGCCGAAGGCAAGC 3225 GCUUGCCUUCGGCUUGCUC 3226 AGCAAGCCGAAGGCAAGCA 3227 UGCUUGCCUUCGGCUUGCU 3228 GCAAGCCGAAGGCAAGCAC 3229 GUGCUUGCCUUCGGCUUGC 3230 CAAGCCGAAGGCAAGCACG 3231 CGUGCUUGCCUUCGGCUUG 3232 AAGCCGAAGGCAAGCACGA 3233 UCGUGCUUGCCUUCGGCUU 3234 AGCCGAAGGCAAGCACGAU 3235 AUCGUGCUUGCCUUCGGCU 3236 GCCGAAGGCAAGCACGAUG 3237 CAUCGUGCUUGCCUUCGGC 3238 AAGGCAAGCACGAUGGCGC 3239 GCGCCAUCGUGCUUGCCUU 3240 AGGCAAGCACGAUGGCGCU 3241 AGCGCCAUCGUGCUUGCCU 3242 AAGCACGAUGGCGCUCACC 3243 GGUGAGCGCCAUCGUGCUU 3244 AGCACGAUGGCGCUCACCA 3245 UGGUGAGCGCCAUCGUGCU 3246 CUGUAGCAGCCGAGCAUCA 3247 UGAUGCUCGGCUGCUACAG 3248 AGCCGAGCAUCAGCCCGAA 3249 UUCGGGCUGAUGCUCGGCU 3250 GUCAGAGUCUCCAGGCUCA 3251 UGAGCCUGGAGACUCUGAC 3252 UCAGAGUCUCCAGGCUCAG 3253 CUGAGCCUGGAGACUCUGA 3254 CAGAGUCUCCAGGCUCAGG 3255 CCUGAGCCUGGAGACUCUG 3256 AGAGUCUCCAGGCUCAGGU 3257 ACCUGAGCCUGGAGACUCU 3258 GAGUCUCCAGGCUCAGGUG 3259 CACCUGAGCCUGGAGACUC 3260 AGUCUCCAGGCUCAGGUGG 3261 CCACCUGAGCCUGGAGACU 3262 GGGUGGCACAGCUGGCAUA 3263 UAUGCCAGCUGUGCCACCC 3264 GUGGCACAGCUGGCAUACG 3265 CGUAUGCCAGCUGUGCCAC 3266 UGGCACAGCUGGCAUACGC 3267 GCGUAUGCCAGCUGUGCCA 3268 CUCCACAGGUGGCGGUAGA 3269 UCUACCGCCACCUGUGGAG 3270 UCCACAGGUGGCGGUAGAC 3271 GUCUACCGCCACCUGUGGA 3272 UGAGCAGCACGCUGGCGUA 3273 UACGCCAGCGUGCUGCUCA 3274 AGCAGCACGCUGGCGUACA 3275 UGUACGCCAGCGUGCUGCU 3276 GCAGCACGCUGGCGUACAU 3277 AUGUACGCCAGCGUGCUGC 3278 CAGCACGCUGGCGUACAUG 3279 CAUGUACGCCAGCGUGCUG 3280 AGCACGCUGGCGUACAUGC 3281 GCAUGUACGCCAGCGUGCU 3282 GCACGCUGGCGUACAUGCU 3283 AGCAUGUACGCCAGCGUGC 3284 CACGCUGGCGUACAUGCUG 3285 CAGCAUGUACGCCAGCGUG 3286 ACGCUGGCGUACAUGCUGA 3287 UCAGCAUGUACGCCAGCGU 3288 CUGGCGUACAUGCUGAGCG 3289 CGCUCAGCAUGUACGCCAG 3290 UGGCGUACAUGCUGAGCGC 3291 GCGCUCAGCAUGUACGCCA 3292 CGCGCACACGUAGUACACC 3293 GGUGUACUACGUGUGCGCG 3294 GCGCACACGUAGUACACCG 3295 CGGUGUACUACGUGUGCGC 3296 CGCACACGUAGUACACCGC 3297 GCGGUGUACUACGUGUGCG 3298 GCACACGUAGUACACCGCC 3299 GGCGGUGUACUACGUGUGC 3300 CACACGUAGUACACCGCCU 3301 AGGCGGUGUACUACGUGUG 3302 ACACGUAGUACACCGCCUU 3303 AAGGCGGUGUACUACGUGU 3304 CACGUAGUACACCGCCUUG 3305 CAAGGCGGUGUACUACGUG 3306 UAGUACACCGCCUUGCAGC 3307 GCUGCAAGGCGGUGUACUA 3308 CCAAGCUCCACACCACGAA 3309 UUCGUGGUGUGGAGCUUGG 3310 CAAGCUCCACACCACGAAG 3311 CUUCGUGGUGUGGAGCUUG 3312 AAGCUCCACACCACGAAGC 3313 GCUUCGUGGUGUGGAGCUU 3314 AGCUCCACACCACGAAGCC 3315 GGCUUCGUGGUGUGGAGCU 3316 CUCCACACCACGAAGCCGU 3317 ACGGCUUCGUGGUGUGGAG 3318 UCCACACCACGAAGCCGUU 3319 AACGGCUUCGUGGUGUGGA 3320 CCACACCACGAAGCCGUUG 3321 CAACGGCUUCGUGGUGUGG 3322 CACACCACGAAGCCGUUGC 3323 GCAACGGCUUCGUGGUGUG 3324 ACACCACGAAGCCGUUGCC 3325 GGCAACGGCUUCGUGGUGU 3326 CACCACGAAGCCGUUGCCA 3327 UGGCAACGGCUUCGUGGUG 3328 ACCACGAAGCCGUUGCCAG 3329 CUGGCAACGGCUUCGUGGU 3330 CCGCGAAGUCUUCCAGCUC 3331 GAGCUGGAAGACUUCGCGG 3332 CGCGAAGUCUUCCAGCUCA 3333 UGAGCUGGAAGACUUCGCG 3334 GCGAAGUCUUCCAGCUCAG 3335 CUGAGCUGGAAGACUUCGC 3336 UUCCAGCUCAGCAGUGUCU 3337 AGACACUGCUGAGCUGGAA 3338 UCCAGCUCAGCAGUGUCUC 3339 GAGACACUGCUGAGCUGGA 3340 CCAGCUCAGCAGUGUCUCG 3341 CGAGACACUGCUGAGCUGG 3342 CAGCUCAGCAGUGUCUCGU 3343 ACGAGACACUGCUGAGCUG 3344 AGCUCAGCAGUGUCUCGUU 3345 AACGAGACACUGCUGAGCU 3346 GCUCAGCAGUGUCUCGUUC 3347 GAACGAGACACUGCUGAGC 3348 CUCAGCAGUGUCUCGUUCC 3349 GGAACGAGACACUGCUGAG 3350 GUAGCAGACCGACAUCCUU 3351 AAGGAUGUCGGUCUGCUAC 3352 UAGCAGACCGACAUCCUUC 3353 GAAGGAUGUCGGUCUGCUA 3354 AGCAGACCGACAUCCUUCU 3355 AGAAGGAUGUCGGUCUGCU 3356 AGACCGACAUCCUUCUGGG 3357 CCCAGAAGGAUGUCGGUCU 3358 GACCGACAUCCUUCUGGGC 3359 GCCCAGAAGGAUGUCGGUC 3360 CCGACAUCCUUCUGGGCCU 3361 AGGCCCAGAAGGAUGUCGG 3362 CGACAUCCUUCUGGGCCUA 3363 UAGGCCCAGAAGGAUGUCG 3364 GACAUCCUUCUGGGCCUAC 3365 GUAGGCCCAGAAGGAUGUC 3366 CUUCUGGGCCUACAGGUGG 3367 CCACCUGUAGGCCCAGAAG 3368 UUCUGGGCCUACAGGUGGG 3369 CCCACCUGUAGGCCCAGAA 3370 UCUGGGCCUACAGGUGGGU 3371 ACCCACCUGUAGGCCCAGA 3372 GGCCUACAGGUGGGUGGAA 3373 UUCCACCCACCUGUAGGCC 3374 CCUACAGGUGGGUGGAAGG 3375 CCUUCCACCCACCUGUAGG 3376 CUACAGGUGGGUGGAAGGC 3377 GCCUUCCACCCACCUGUAG 3378 UACAGGUGGGUGGAAGGCG 3379 CGCCUUCCACCCACCUGUA 3380 ACUUCCCUGCAGCCUGCCU 3381 AGGCAGGCUGCAGGGAAGU 3382 CCUGCAGCCUGCCUCUUUU 3383 AAAAGAGGCAGGCUGCAGG 3384 CUGCAGCCUGCCUCUUUUC 3385 GAAAAGAGGCAGGCUGCAG 3386 GCAGCCUGCCUCUUUUCUG 3387 CAGAAAAGAGGCAGGCUGC 3388 CAGCCUGCCUCUUUUCUGC 3389 GCAGAAAAGAGGCAGGCUG 3390 AGCCUGCCUCUUUUCUGCC 3391 GGCAGAAAAGAGGCAGGCU 3392 GCCUCUUUUCUGCCUGGGA 3393 UCCCAGGCAGAAAAGAGGC 3394 CUUUUCUGCCUGGGAGUCC 3395 GGACUCCCAGGCAGAAAAG 3396 UUUUCUGCCUGGGAGUCCU 3397 AGGACUCCCAGGCAGAAAA 3398 UUCUGCCUGGGAGUCCUGA 3399 UCAGGACUCCCAGGCAGAA 3400 UCUGCCUGGGAGUCCUGAC 3401 GUCAGGACUCCCAGGCAGA 3402 UGCCUGGGAGUCCUGACUU 3403 AAGUCAGGACUCCCAGGCA 3404 GCCUGGGAGUCCUGACUUC 3405 GAAGUCAGGACUCCCAGGC 3406 CUGGGAGUCCUGACUUCCA 3407 UGGAAGUCAGGACUCCCAG 3408 UGGGAGUCCUGACUUCCAC 3409 GUGGAAGUCAGGACUCCCA 3410 GGGAGUCCUGACUUCCACG 3411 CGUGGAAGUCAGGACUCCC 3412 GGAGUCCUGACUUCCACGA 3413 UCGUGGAAGUCAGGACUCC 3414 GAGUCCUGACUUCCACGAG 3415 CUCGUGGAAGUCAGGACUC 3416 AGUCCUGACUUCCACGAGG 3417 CCUCGUGGAAGUCAGGACU 3418 CCUGACUUCCACGAGGACC 3419 GGUCCUCGUGGAAGUCAGG 3420 CUGACUUCCACGAGGACCC 3421 GGGUCCUCGUGGAAGUCAG 3422 UGACUUCCACGAGGACCCA 3423 UGGGUCCUCGUGGAAGUCA 3424 GACUUCCACGAGGACCCAG 3425 CUGGGUCCUCGUGGAAGUC 3426 ACUUCCACGAGGACCCAGA 3427 UCUGGGUCCUCGUGGAAGU 3428 CUUCCACGAGGACCCAGAC 3429 GUCUGGGUCCUCGUGGAAG 3430 UUCCACGAGGACCCAGACC 3431 GGUCUGGGUCCUCGUGGAA 3432 CCCUGCUCCCAGUCAGUUG 3433 CAACUGACUGGGAGCAGGG 3434 CCUGCUCCCAGUCAGUUGA 3435 UCAACUGACUGGGAGCAGG 3436 CUGCUCCCAGUCAGUUGAC 3437 GUCAACUGACUGGGAGCAG 3438 UGCUCCCAGUCAGUUGACC 3439 GGUCAACUGACUGGGAGCA 3440 CCCAGUCAGUUGACCUGCC 3441 GGCAGGUCAACUGACUGGG 3442 CCAGUCAGUUGACCUGCCC 3443 GGGCAGGUCAACUGACUGG 3444 GCCUCCUUCCCAGAGCUCA 3445 UGAGCUCUGGGAAGGAGGC 3446 CCUCCUUCCCAGAGCUCAG 3447 CUGAGCUCUGGGAAGGAGG 3448 CUCCUUCCCAGAGCUCAGU 3449 ACUGAGCUCUGGGAAGGAG 3450 UCCUUCCCAGAGCUCAGUG 3451 CACUGAGCUCUGGGAAGGA 3452 CCUUCCCAGAGCUCAGUGG 3453 CCACUGAGCUCUGGGAAGG 3454 UUCCCAGAGCUCAGUGGUA 3455 UACCACUGAGCUCUGGGAA 3456 UCCCAGAGCUCAGUGGUAA 3457 UUACCACUGAGCUCUGGGA 3458 CAGGCUGUCACUAUCUCUA 3459 UAGAGAUAGUGACAGCCUG 3460 AGGCUGUCACUAUCUCUAC 3461 GUAGAGAUAGUGACAGCCU 3462 UCUCUACCACCACUCCUCU 3463 AGAGGAGUGGUGGUAGAGA 3464 CCACCACUCCUCUAGUCUG 3465 CAGACUAGAGGAGUGGUGG 3466 CACCACUCCUCUAGUCUGG 3467 CCAGACUAGAGGAGUGGUG 3468 ACCACUCCUCUAGUCUGGC 3469 GCCAGACUAGAGGAGUGGU 3470 CCACUCCUCUAGUCUGGCC 3471 GGCCAGACUAGAGGAGUGG 3472 CACUCCUCUAGUCUGGCCC 3473 GGGCCAGACUAGAGGAGUG 3474 AUUCUAGCACAUCUGGGCA 3475 UGCCCAGAUGUGCUAGAAU 3476 UUCUAGCACAUCUGGGCAA 3477 UUGCCCAGAUGUGCUAGAA 3478 UCUAGCACAUCUGGGCAAA 3479 UUUGCCCAGAUGUGCUAGA 3480 CUAGCACAUCUGGGCAAAA 3481 UUUUGCCCAGAUGUGCUAG 3482 GGGUGUAAAGGGACGUGCA 3483 UGCACGUCCCUUUACACCC 3484 GGUGUAAAGGGACGUGCAC 3485 GUGCACGUCCCUUUACACC 3486 GUGUAAAGGGACGUGCACA 3487 UGUGCACGUCCCUUUACAC 3488 UGUAAAGGGACGUGCACAG 3489 CUGUGCACGUCCCUUUACA 3490 GUAAAGGGACGUGCACAGA 3491 UCUGUGCACGUCCCUUUAC 3492 UAAAGGGACGUGCACAGAU 3493 AUCUGUGCACGUCCCUUUA 3494 AAAGGGACGUGCACAGAUC 3495 GAUCUGUGCACGUCCCUUU 3496 AAGGGACGUGCACAGAUCU 3497 AGAUCUGUGCACGUCCCUU 3498 AGGGACGUGCACAGAUCUA 3499 UAGAUCUGUGCACGUCCCU 3500 CGUGCACAGAUCUACUUAC 3501 GUAAGUAGAUCUGUGCACG 3502 GUGCACAGAUCUACUUACC 3503 GGUAAGUAGAUCUGUGCAC 3504 UGCACAGAUCUACUUACCA 3505 UGGUAAGUAGAUCUGUGCA 3506 GCACAGAUCUACUUACCAA 3507 UUGGUAAGUAGAUCUGUGC 3508 CACAGAUCUACUUACCAAG 3509 CUUGGUAAGUAGAUCUGUG 3510 ACAGAUCUACUUACCAAGC 3511 GCUUGGUAAGUAGAUCUGU 3512 CAGAUCUACUUACCAAGCU 3513 AGCUUGGUAAGUAGAUCUG 3514 AGAUCUACUUACCAAGCUG 3515 CAGCUUGGUAAGUAGAUCU 3516 AUCUACUUACCAAGCUGGG 3517 CCCAGCUUGGUAAGUAGAU 3518 UCUACUUACCAAGCUGGGA 3519 UCCCAGCUUGGUAAGUAGA 3520 CUUACCAAGCUGGGAGCAA 3521 UUGCUCCCAGCUUGGUAAG 3522 UUACCAAGCUGGGAGCAAG 3523 CUUGCUCCCAGCUUGGUAA 3524 UACCAAGCUGGGAGCAAGC 3525 GCUUGCUCCCAGCUUGGUA 3526 ACCAAGCUGGGAGCAAGCA 3527 UGCUUGCUCCCAGCUUGGU 3528 GCUGGGAGCAAGCAGGAUU 3529 AAUCCUGCUUGCUCCCAGC 3530 CUGGGAGCAAGCAGGAUUG 3531 CAAUCCUGCUUGCUCCCAG 3532 UGGGAGCAAGCAGGAUUGG 3533 CCAAUCCUGCUUGCUCCCA 3534 GGGAGCAAGCAGGAUUGGG 3535 CCCAAUCCUGCUUGCUCCC 3536 AAAGGUUAAGCAGCAGUAG 3537 CUACUGCUGCUUAACCUUU 3538 AAGGUUAAGCAGCAGUAGG 3539 CCUACUGCUGCUUAACCUU 3540 AGGUUAAGCAGCAGUAGGC 3541 GCCUACUGCUGCUUAACCU 3542 GGUGCCUACUCCUGUCCUG 3543 CAGGACAGGAGUAGGCACC 3544 GUGCCUACUCCUGUCCUGU 3545 ACAGGACAGGAGUAGGCAC 3546 UGCCUACUCCUGUCCUGUG 3547 CACAGGACAGGAGUAGGCA 3548 GCCUACUCCUGUCCUGUGC 3549 GCACAGGACAGGAGUAGGC 3550 CCUACUCCUGUCCUGUGCC 3551 GGCACAGGACAGGAGUAGG 3552 CUACUCCUGUCCUGUGCCU 3553 AGGCACAGGACAGGAGUAG 3554 UACUCCUGUCCUGUGCCUA 3555 UAGGCACAGGACAGGAGUA 3556 ACUCCUGUCCUGUGCCUAU 3557 AUAGGCACAGGACAGGAGU 3558 CUCCUGUCCUGUGCCUAUC 3559 GAUAGGCACAGGACAGGAG 3560 UCCUGUCCUGUGCCUAUCA 3561 UGAUAGGCACAGGACAGGA 3562 GUGCCUAUCACAUUUGCAG 3563 CUGCAAAUGUGAUAGGCAC 3564 CUAUCACAUUUGCAGAGGG 3565 CCCUCUGCAAAUGUGAUAG 3566 UAUCACAUUUGCAGAGGGU 3567 ACCCUCUGCAAAUGUGAUA 3568 AUCACAUUUGCAGAGGGUA 3569 UACCCUCUGCAAAUGUGAU 3570 UCACAUUUGCAGAGGGUAA 3571 UUACCCUCUGCAAAUGUGA 3572 CACAUUUGCAGAGGGUAAG 3573 CUUACCCUCUGCAAAUGUG 3574 ACAUUUGCAGAGGGUAAGA 3575 UCUUACCCUCUGCAAAUGU 3576 CUCACCCUGCUCCUUCCCA 3577 UGGGAAGGAGCAGGGUGAG 3578 CACCCUGCUCCUUCCCAUC 3579 GAUGGGAAGGAGCAGGGUG 3580 CCUGCUCCUUCCCAUCACC 3581 GGUGAUGGGAAGGAGCAGG 3582 UGCUCCUUCCCAUCACCAA 3583 UUGGUGAUGGGAAGGAGCA 3584 CAGUAAGAUUCCCUGGUGG 3585 CCACCAGGGAAUCUUACUG 3586 AGUAAGAUUCCCUGGUGGU 3587 ACCACCAGGGAAUCUUACU 3588 GUAAGAUUCCCUGGUGGUG 3589 CACCACCAGGGAAUCUUAC 3590 UAAGAUUCCCUGGUGGUGG 3591 CCACCACCAGGGAAUCUUA 3592 AAGAUUCCCUGGUGGUGGA 3593 UCCACCACCAGGGAAUCUU 3594 UCCCUGGUGGUGGAAGGAA 3595 UUCCUUCCACCACCAGGGA 3596 UCUGCUGAAUCCUGGUCCU 3597 AGGACCAGGAUUCAGCAGA 3598 CUGCUGAAUCCUGGUCCUG 3599 CAGGACCAGGAUUCAGCAG 3600 UGCUGAAUCCUGGUCCUGC 3601 GCAGGACCAGGAUUCAGCA 3602 UGAAUCCUGGUCCUGCUUC 3603 GAAGCAGGACCAGGAUUCA 3604 GAAUCCUGGUCCUGCUUCU 3605 AGAAGCAGGACCAGGAUUC 3606 AAUCCUGGUCCUGCUUCUG 3607 CAGAAGCAGGACCAGGAUU 3608 AUCCUGGUCCUGCUUCUGU 3609 ACAGAAGCAGGACCAGGAU 3610 UCCUGGUCCUGCUUCUGUU 3611 AACAGAAGCAGGACCAGGA 3612 CCUGGUCCUGCUUCUGUUC 3613 GAACAGAAGCAGGACCAGG 3614 CUGGUCCUGCUUCUGUUCU 3615 AGAACAGAAGCAGGACCAG 3616 UUCUGUUCUCAUCCCUCCC 3617 GGGAGGGAUGAGAACAGAA 3618 CUUCUGCAGUGUGUAUGUU 3619 AACAUACACACUGCAGAAG 3620 UUCUGCAGUGUGUAUGUUG 3621 CAACAUACACACUGCAGAA 3622 UCUGCAGUGUGUAUGUUGC 3623 GCAACAUACACACUGCAGA 3624 CUGCAGUGUGUAUGUUGCC 3625 GGCAACAUACACACUGCAG 3626 UGCAGUGUGUAUGUUGCCU 3627 AGGCAACAUACACACUGCA 3628 GCAGUGUGUAUGUUGCCUG 3629 CAGGCAACAUACACACUGC 3630 CAGUGUGUAUGUUGCCUGG 3631 CCAGGCAACAUACACACUG 3632 AGUGUGUAUGUUGCCUGGU 3633 ACCAGGCAACAUACACACU 3634 GUGUGUAUGUUGCCUGGUC 3635 GACCAGGCAACAUACACAC 3636 UGUGUAUGUUGCCUGGUCU 3637 AGACCAGGCAACAUACACA 3638 GUGUAUGUUGCCUGGUCUC 3639 GAGACCAGGCAACAUACAC 3640 UGUAUGUUGCCUGGUCUCU 3641 AGAGACCAGGCAACAUACA 3642 GUAUGUUGCCUGGUCUCUC 3643 GAGAGACCAGGCAACAUAC 3644 UAUGUUGCCUGGUCUCUCU 3645 AGAGAGACCAGGCAACAUA 3646 AUGUUGCCUGGUCUCUCUG 3647 CAGAGAGACCAGGCAACAU 3648 UGUUGCCUGGUCUCUCUGG 3649 CCAGAGAGACCAGGCAACA 3650 GUUGCCUGGUCUCUCUGGC 3651 GCCAGAGAGACCAGGCAAC 3652 UUGCCUGGUCUCUCUGGCC 3653 GGCCAGAGAGACCAGGCAA 3654 CUGGUCUCUCUGGCCUGCA 3655 UGCAGGCCAGAGAGACCAG 3656 CCUGCAGAGGUGACCCAAA 3657 UUUGGGUCACCUCUGCAGG 3658 CUGCCUUAUCCUUGCCUGU 3659 ACAGGCAAGGAUAAGGCAG 3660 UGCCUUAUCCUUGCCUGUU 3661 AACAGGCAAGGAUAAGGCA 3662 GCCUUAUCCUUGCCUGUUU 3663 AAACAGGCAAGGAUAAGGC 3664 AGUCUCCUGGUCCGGCUGA 3665 UCAGCCGGACCAGGAGACU 3666 GUCAAUGACAGCUUUUCCA 3667 UGGAAAAGCUGUCAUUGAC 3668 UGACAGCUUUUCCAUGUAA 3669 UUACAUGGAAAAGCUGUCA 3670 GACAGCUUUUCCAUGUAAG 3671 CUUACAUGGAAAAGCUGUC 3672 ACAGCUUUUCCAUGUAAGG 3673 CCUUACAUGGAAAAGCUGU 3674 CAGCUUUUCCAUGUAAGGC 3675 GCCUUACAUGGAAAAGCUG 3676 AGCUUUUCCAUGUAAGGCA 3677 UGCCUUACAUGGAAAAGCU 3678 UGUAAGGCAUGGUGCUAGG 3679 CCUAGCACCAUGCCUUACA 3680 GUAAGGCAUGGUGCUAGGU 3681 ACCUAGCACCAUGCCUUAC 3682 UAAGGCAUGGUGCUAGGUU 3683 AACCUAGCACCAUGCCUUA 3684 GCAUGGUGCUAGGUUCCAG 3685 CUGGAACCUAGCACCAUGC 3686 CAUGGUGCUAGGUUCCAGG 3687 CCUGGAACCUAGCACCAUG 3688 AUGGUGCUAGGUUCCAGGA 3689 UCCUGGAACCUAGCACCAU 3690 UGGUGCUAGGUUCCAGGAG 3691 CUCCUGGAACCUAGCACCA 3692 GGUGCUAGGUUCCAGGAGG 3693 CCUCCUGGAACCUAGCACC 3694 GUGCUAGGUUCCAGGAGGA 3695 UCCUCCUGGAACCUAGCAC 3696 UGCAUGGAGGCAUAAUGGU 3697 ACCAUUAUGCCUCCAUGCA 3698 GCAUGGAGGCAUAAUGGUU 3699 AACCAUUAUGCCUCCAUGC 3700 CAUGGAGGCAUAAUGGUUA 3701 UAACCAUUAUGCCUCCAUG 3702 AUGGAGGCAUAAUGGUUAG 3703 CUAACCAUUAUGCCUCCAU 3704 UGGAGGCAUAAUGGUUAGG 3705 CCUAACCAUUAUGCCUCCA 3706 GGAGGCAUAAUGGUUAGGG 3707 CCCUAACCAUUAUGCCUCC 3708 GAGGCAUAAUGGUUAGGGA 3709 UCCCUAACCAUUAUGCCUC 3710 CAUAAUGGUUAGGGAGUCA 3711 UGACUCCCUAACCAUUAUG 3712 AUAAUGGUUAGGGAGUCAU 3713 AUGACUCCCUAACCAUUAU 3714 UAAUGGUUAGGGAGUCAUG 3715 CAUGACUCCCUAACCAUUA 3716 GGUUAGGGAGUCAUGACAC 3717 GUGUCAUGACUCCCUAACC 3718 CAUUACCAGGCUGCACCAG 3719 CUGGUGCAGCCUGGUAAUG 3720 AUUACCAGGCUGCACCAGG 3721 CCUGGUGCAGCCUGGUAAU 3722 UACCAGGCUGCACCAGGAU 3723 AUCCUGGUGCAGCCUGGUA 3724 ACCAGGCUGCACCAGGAUA 3725 UAUCCUGGUGCAGCCUGGU 3726 CCAGGCUGCACCAGGAUAC 3727 GUAUCCUGGUGCAGCCUGG 3728 AAAGGAUGAGUAGGGACAU 3729 AUGUCCCUACUCAUCCUUU 3730 AAGGAUGAGUAGGGACAUA 3731 UAUGUCCCUACUCAUCCUU 3732 AGGAUGAGUAGGGACAUAC 3733 GUAUGUCCCUACUCAUCCU 3734 GUAGGGACAUACUAAGAAG 3735 CUUCUUAGUAUGUCCCUAC 3736 GGACAUACUAAGAAGCAGC 3737 GCUGCUUCUUAGUAUGUCC 3738 AUACUAAGAAGCAGCCCUC 3739 GAGGGCUGCUUCUUAGUAU 3740 UACUAAGAAGCAGCCCUCU 3741 AGAGGGCUGCUUCUUAGUA 3742 ACUAAGAAGCAGCCCUCUC 3743 GAGAGGGCUGCUUCUUAGU 3744 AGAAGCAGCCCUCUCCUCU 3745 AGAGGAGAGGGCUGCUUCU 3746 GAAGCAGCCCUCUCCUCUU 3747 AAGAGGAGAGGGCUGCUUC 3748 CAGCCCUCUCCUCUUGGAA 3749 UUCCAAGAGGAGAGGGCUG 3750 GCCUGGCAGAUGGAUAGAG 3751 CUCUAUCCAUCUGCCAGGC 3752 CCUGGCAGAUGGAUAGAGC 3753 GCUCUAUCCAUCUGCCAGG 3754 CUGGCAGAUGGAUAGAGCU 3755 AGCUCUAUCCAUCUGCCAG 3756 UGGCAGAUGGAUAGAGCUG 3757 CAGCUCUAUCCAUCUGCCA 3758 GGCAGAUGGAUAGAGCUGG 3759 CCAGCUCUAUCCAUCUGCC 3760 GCAGAUGGAUAGAGCUGGG 3761 CCCAGCUCUAUCCAUCUGC 3762 AAAGGCCUCUGCUCAAGUA 3763 UACUUGAGCAGAGGCCUUU 3764 AAGGCCUCUGCUCAAGUAA 3765 UUACUUGAGCAGAGGCCUU 3766 AGGCCUCUGCUCAAGUAAC 3767 GUUACUUGAGCAGAGGCCU 3768 CAGGAGCACUGUCUUAGUU 3769 AACUAAGACAGUGCUCCUG 3770 AGGAGCACUGUCUUAGUUU 3771 AAACUAAGACAGUGCUCCU 3772 GGAGCACUGUCUUAGUUUG 3773 CAAACUAAGACAGUGCUCC 3774 GAGCACUGUCUUAGUUUGG 3775 CCAAACUAAGACAGUGCUC 3776 AGCACUGUCUUAGUUUGGG 3777 CCCAAACUAAGACAGUGCU 3778 GUUCUUCCAAAGCAGAGCU 3779 AGCUCUGCUUUGGAAGAAC 3780 AGCAGAGCUUGAGCUAAGG 3781 CCUUAGCUCAAGCUCUGCU 3782 GCAGAGCUUGAGCUAAGGG 3783 CCCUUAGCUCAAGCUCUGC 3784 CAGAGCUUGAGCUAAGGGC 3785 GCCCUUAGCUCAAGCUCUG 3786 GCUUGAGCUAAGGGCUUGG 3787 CCAAGCCCUUAGCUCAAGC 3788 UUGAGCUAAGGGCUUGGGU 3789 ACCCAAGCCCUUAGCUCAA 3790 UGAGCUAAGGGCUUGGGUA 3791 UACCCAAGCCCUUAGCUCA 3792 GAGCUAAGGGCUUGGGUAC 3793 GUACCCAAGCCCUUAGCUC 3794 AGCUAAGGGCUUGGGUACA 3795 UGUACCCAAGCCCUUAGCU 3796 GCUAAGGGCUUGGGUACAG 3797 CUGUACCCAAGCCCUUAGC 3798 AGGGCUUGGGUACAGGUGA 3799 UCACCUGUACCCAAGCCCU 3800 GGGCUUGGGUACAGGUGAU 3801 AUCACCUGUACCCAAGCCC 3802 GGCUUGGGUACAGGUGAUC 3803 GAUCACCUGUACCCAAGCC 3804 GCUUGGGUACAGGUGAUCC 3805 GGAUCACCUGUACCCAAGC 3806 AGGUGAUCCUGUAUUCUUG 3807 CAAGAAUACAGGAUCACCU 3808 GGUGAUCCUGUAUUCUUGA 3809 UCAAGAAUACAGGAUCACC 3810 GUGAUCCUGUAUUCUUGAG 3811 CUCAAGAAUACAGGAUCAC 3812 UGAUCCUGUAUUCUUGAGC 3813 GCUCAAGAAUACAGGAUCA 3814 UCCUGUAUUCUUGAGCUAA 3815 UUAGCUCAAGAAUACAGGA 3816 CCUGUAUUCUUGAGCUAAG 3817 CUUAGCUCAAGAAUACAGG 3818 UGUAUUCUUGAGCUAAGGG 3819 CCCUUAGCUCAAGAAUACA 3820 GUAUUCUUGAGCUAAGGGC 3821 GCCCUUAGCUCAAGAAUAC 3822 UCUUGAGCUAAGGGCUUGG 3823 CCAAGCCCUUAGCUCAAGA 3824 UUGAGCUAAGGGCUUGGGU 3825 ACCCAAGCCCUUAGCUCAA 3826 UGAGCUAAGGGCUUGGGUA 3827 UACCCAAGCCCUUAGCUCA 3828 GAGCUAAGGGCUUGGGUAC 3829 GUACCCAAGCCCUUAGCUC 3830 AGCUAAGGGCUUGGGUACA 3831 UGUACCCAAGCCCUUAGCU 3832 GCUAAGGGCUUGGGUACAG 3833 CUGUACCCAAGCCCUUAGC 3834 AGGGCUUGGGUACAGGUGA 3835 UCACCUGUACCCAAGCCCU 3836 GGGCUUGGGUACAGGUGAU 3837 AUCACCUGUACCCAAGCCC 3838 GGCUUGGGUACAGGUGAUC 3839 GAUCACCUGUACCCAAGCC 3840 GCUUGGGUACAGGUGAUCC 3841 GGAUCACCUGUACCCAAGC 3842 AGGUGAUCCUGUAUUUGGG 3843 CCCAAAUACAGGAUCACCU 3844 GGUGAUCCUGUAUUUGGGA 3845 UCCCAAAUACAGGAUCACC 3846 AUCCUGUAUUUGGGAGGUU 3847 AACCUCCCAAAUACAGGAU 3848 UCCUGUAUUUGGGAGGUUA 3849 UAACCUCCCAAAUACAGGA 3850 CCUGUAUUUGGGAGGUUAA 3851 UUAACCUCCCAAAUACAGG 3852 CUGUAUUUGGGAGGUUAAC 3853 GUUAACCUCCCAAAUACAG 3854 UGUAUUUGGGAGGUUAACU 3855 AGUUAACCUCCCAAAUACA 3856 GUAUUUGGGAGGUUAACUC 3857 GAGUUAACCUCCCAAAUAC 3858 UAUUUGGGAGGUUAACUCA 3859 UGAGUUAACCUCCCAAAUA 3860 GGAGGUUAACUCAGGAAGU 3861 ACUUCCUGAGUUAACCUCC 3862 GAGGUUAACUCAGGAAGUG 3863 CACUUCCUGAGUUAACCUC 3864 AGGUUAACUCAGGAAGUGA 3865 UCACUUCCUGAGUUAACCU 3866 UCAGGAAGUGAGGGCAUAA 3867 UUAUGCCCUCACUUCCUGA 3868 CAGGAAGUGAGGGCAUAAG 3869 CUUAUGCCCUCACUUCCUG 3870 AGGAAGUGAGGGCAUAAGG 3871 CCUUAUGCCCUCACUUCCU 3872 GGAAGUGAGGGCAUAAGGU 3873 ACCUUAUGCCCUCACUUCC 3874 GAAGUGAGGGCAUAAGGUA 3875 UACCUUAUGCCCUCACUUC 3876 AAGUGAGGGCAUAAGGUAA 3877 UUACCUUAUGCCCUCACUU 3878 AGUGAGGGCAUAAGGUAAA 3879 UUUACCUUAUGCCCUCACU 3880 AAAGCCAUUAAGAGUAUGU 3881 ACAUACUCUUAAUGGCUUU 3882 AAGCCAUUAAGAGUAUGUU 3883 AACAUACUCUUAAUGGCUU 3884 AGCCAUUAAGAGUAUGUUA 3885 UAACAUACUCUUAAUGGCU 3886 UAAGAGUAUGUUAAGUCCC 3887 GGGACUUAACAUACUCUUA 3888 AAGAGUAUGUUAAGUCCCU 3889 AGGGACUUAACAUACUCUU 3890 AGAGUAUGUUAAGUCCCUU 3891 AAGGGACUUAACAUACUCU 3892 GAGUAUGUUAAGUCCCUUC 3893 GAAGGGACUUAACAUACUC 3894 AGUAUGUUAAGUCCCUUCA 3895 UGAAGGGACUUAACAUACU 3896 GUAUGUUAAGUCCCUUCAG 3897 CUGAAGGGACUUAACAUAC 3898 UAUGUUAAGUCCCUUCAGU 3899 ACUGAAGGGACUUAACAUA 3900 AUGUUAAGUCCCUUCAGUA 3901 UACUGAAGGGACUUAACAU 3902 UGUUAAGUCCCUUCAGUAG 3903 CUACUGAAGGGACUUAACA 3904 GUUAAGUCCCUUCAGUAGG 3905 CCUACUGAAGGGACUUAAC 3906 UUAAGUCCCUUCAGUAGGC 3907 GCCUACUGAAGGGACUUAA 3908 UAAGUCCCUUCAGUAGGCC 3909 GGCCUACUGAAGGGACUUA 3910 AAGUCCCUUCAGUAGGCCU 3911 AGGCCUACUGAAGGGACUU 3912 AGUCCCUUCAGUAGGCCUU 3913 AAGGCCUACUGAAGGGACU 3914 GUCCCUUCAGUAGGCCUUG 3915 CAAGGCCUACUGAAGGGAC 3916 UCCCUUCAGUAGGCCUUGG 3917 CCAAGGCCUACUGAAGGGA 3918 CCCUUCAGUAGGCCUUGGG 3919 CCCAAGGCCUACUGAAGGG 3920 CCUUCAGUAGGCCUUGGGA 3921 UCCCAAGGCCUACUGAAGG 3922 CUUCAGUAGGCCUUGGGAA 3923 UUCCCAAGGCCUACUGAAG 3924 AAAAGUAUAGAUUGCCCAA 3925 UUGGGCAAUCUAUACUUUU 3926 AAAGUAUAGAUUGCCCAAG 3927 CUUGGGCAAUCUAUACUUU 3928 AAGUAUAGAUUGCCCAAGA 3929 UCUUGGGCAAUCUAUACUU 3930 AAAGACUGGCAGGGUGAUC 3931 GAUCACCCUGCCAGUCUUU 3932 AAGACUGGCAGGGUGAUCA 3933 UGAUCACCCUGCCAGUCUU 3934 CUGGCAGGGUGAUCAGUCC 3935 GGACUGAUCACCCUGCCAG 3936 GAAUGUACUUAAUGAGUGG 3937 CCACUCAUUAAGUACAUUC 3938 AAUGUACUUAAUGAGUGGG 3939 CCCACUCAUUAAGUACAUU 3940 UGUACUUAAUGAGUGGGCU 3941 AGCCCACUCAUUAAGUACA 3942 GUACUUAAUGAGUGGGCUA 3943 UAGCCCACUCAUUAAGUAC 3944 UACUUAAUGAGUGGGCUAC 3945 GUAGCCCACUCAUUAAGUA 3946 CUUAAUGAGUGGGCUACAG 3947 CUGUAGCCCACUCAUUAAG 3948 UAAUGAGUGGGCUACAGCG 3949 CGCUGUAGCCCACUCAUUA 3950 AAUGAGUGGGCUACAGCGU 3951 ACGCUGUAGCCCACUCAUU 3952 AUGAGUGGGCUACAGCGUA 3953 UACGCUGUAGCCCACUCAU 3954 UGAGUGGGCUACAGCGUAU 3955 AUACGCUGUAGCCCACUCA 3956 GAGUGGGCUACAGCGUAUC 3957 GAUACGCUGUAGCCCACUC 3958 AGUGGGCUACAGCGUAUCC 3959 GGAUACGCUGUAGCCCACU 3960 GUGGGCUACAGCGUAUCCU 3961 AGGAUACGCUGUAGCCCAC 3962 UGGGCUACAGCGUAUCCUC 3963 GAGGAUACGCUGUAGCCCA 3964 AGAGUUGUUCUACCUGGGU 3965 ACCCAGGUAGAACAACUCU 3966 GAGUUGUUCUACCUGGGUA 3967 UACCCAGGUAGAACAACUC 3968 AGUUGUUCUACCUGGGUAU 3969 AUACCCAGGUAGAACAACU 3970 GUUGUUCUACCUGGGUAUA 3971 UAUACCCAGGUAGAACAAC 3972 UUGUUCUACCUGGGUAUAU 3973 AUAUACCCAGGUAGAACAA 3974 UGUUCUACCUGGGUAUAUC 3975 GAUAUACCCAGGUAGAACA 3976 GUUCUACCUGGGUAUAUCC 3977 GGAUAUACCCAGGUAGAAC 3978 UACCUGGGUAUAUCCAAAA 3979 UUUUGGAUAUACCCAGGUA 3980 AGGGUAUGGAGUUUACGAG 3981 CUCGUAAACUCCAUACCCU 3982 GGGUAUGGAGUUUACGAGG 3983 CCUCGUAAACUCCAUACCC 3984 GGUAUGGAGUUUACGAGGG 3985 CCCUCGUAAACUCCAUACC 3986 GUAUGGAGUUUACGAGGGU 3987 ACCCUCGUAAACUCCAUAC 3988 UAUGGAGUUUACGAGGGUU 3989 AACCCUCGUAAACUCCAUA 3990 AUGGAGUUUACGAGGGUUC 3991 GAACCCUCGUAAACUCCAU 3992 UGGAGUUUACGAGGGUUCA 3993 UGAACCCUCGUAAACUCCA 3994 GGAGUUUACGAGGGUUCAA 3995 UUGAACCCUCGUAAACUCC 3996 GAGUUUACGAGGGUUCAAG 3997 CUUGAACCCUCGUAAACUC 3998 AGUUUACGAGGGUUCAAGG 3999 CCUUGAACCCUCGUAAACU 4000 GUUUACGAGGGUUCAAGGU 4001 ACCUUGAACCCUCGUAAAC 4002 UUUACGAGGGUUCAAGGUA 4003 UACCUUGAACCCUCGUAAA 4004 CGAGGGUUCAAGGUAUUUG 4005 CAAAUACCUUGAACCCUCG 4006 GAGGGUUCAAGGUAUUUGG 4007 CCAAAUACCUUGAACCCUC 4008 AGGGUUCAAGGUAUUUGGU 4009 ACCAAAUACCUUGAACCCU 4010 GGGUUCAAGGUAUUUGGUU 4011 AACCAAAUACCUUGAACCC 4012 GGUUCAAGGUAUUUGGUUC 4013 GAACCAAAUACCUUGAACC 4014 GUUCAAGGUAUUUGGUUCA 4015 UGAACCAAAUACCUUGAAC 4016 UUCAAGGUAUUUGGUUCAG 4017 CUGAACCAAAUACCUUGAA 4018 UCAAGGUAUUUGGUUCAGG 4019 CCUGAACCAAAUACCUUGA 4020 CAACUGGCCAGGUCACAGG 4021 CCUGUGACCUGGCCAGUUG 4022 GCCAGGUCACAGGGCAAUC 4023 GAUUGCCCUGUGACCUGGC 4024 CCAGGUCACAGGGCAAUCA 4025 UGAUUGCCCUGUGACCUGG 4026 AGGUCACAGGGCAAUCAAG 4027 CUUGAUUGCCCUGUGACCU 4028 GGUCACAGGGCAAUCAAGU 4029 ACUUGAUUGCCCUGUGACC 4030 GUCACAGGGCAAUCAAGUU 4031 AACUUGAUUGCCCUGUGAC 4032 UCACAGGGCAAUCAAGUUA 4033 UAACUUGAUUGCCCUGUGA 4034 CACAGGGCAAUCAAGUUAC 4035 GUAACUUGAUUGCCCUGUG 4036 ACAGGGCAAUCAAGUUACU 4037 AGUAACUUGAUUGCCCUGU 4038 CAGGGCAAUCAAGUUACUC 4039 GAGUAACUUGAUUGCCCUG 4040 AGGGCAAUCAAGUUACUCU 4041 AGAGUAACUUGAUUGCCCU 4042 CAAUCAAGUUACUCUGUGU 4043 ACACAGAGUAACUUGAUUG 4044 AAUCAAGUUACUCUGUGUU 4045 AACACAGAGUAACUUGAUU 4046 AUCAAGUUACUCUGUGUUU 4047 AAACACAGAGUAACUUGAU 4048 ACUCUGUGUUUCUUUGUCA 4049 UGACAAAGAAACACAGAGU 4050 UCUGUGUUUCUUUGUCAGG 4051 CCUGACAAAGAAACACAGA 4052 UGUUUCUUUGUCAGGACAC 4053 GUGUCCUGACAAAGAAACA 4054 AAAGCAGGGAUUGUGUUCA 4055 UGAACACAAUCCCUGCUUU 4056 AAGCAGGGAUUGUGUUCAU 4057 AUGAACACAAUCCCUGCUU 4058 AGCAGGGAUUGUGUUCAUU 4059 AAUGAACACAAUCCCUGCU 4060 GCAGGGAUUGUGUUCAUUU 4061 AAAUGAACACAAUCCCUGC 4062 CAGGGAUUGUGUUCAUUUG 4063 CAAAUGAACACAAUCCCUG 4064 AGGGAUUGUGUUCAUUUGA 4065 UCAAAUGAACACAAUCCCU 4066 GUGUUCAUUUGAGGGUUUC 4067 GAAACCCUCAAAUGAACAC 4068 UGUUCAUUUGAGGGUUUCA 4069 UGAAACCCUCAAAUGAACA 4070 GUUCAUUUGAGGGUUUCAC 4071 GUGAAACCCUCAAAUGAAC 4072 UUCAUUUGAGGGUUUCACU 4079 AGUGAAACCCUCAAAUGAA 4074 UCAUUUGAGGGUUUCACUG 4075 CAGUGAAACCCUCAAAUGA 4076 CAUUUGAGGGUUUCACUGU 4077 ACAGUGAAACCCUCAAAUG 4078 AGUCUCAGCUUCCAUGCAA 4079 UUGCAUGGAAGCUGAGACU 4080 UCUCAGCUUCCAUGCAACU 4081 AGUUGCAUGGAAGCUGAGA 4082 CUCAGCUUCCAUGCAACUG 4083 CAGUUGCAUGGAAGCUGAG 4084 UCAGCUUCCAUGCAACUGU 4085 ACAGUUGCAUGGAAGCUGA 4086 CAGCUUCCAUGCAACUGUC 4087 GACAGUUGCAUGGAAGCUG 4088 AGCUUCCAUGCAACUGUCC 4089 GGACAGUUGCAUGGAAGCU 4090 GCUUCCAUGCAACUGUCCA 4091 UGGACAGUUGCAUGGAAGC 4092 CUUCCAUGCAACUGUCCAU 4093 AUGGACAGUUGCAUGGAAG 4094 UUCCAUGCAACUGUCCAUC 4095 GAUGGACAGUUGCAUGGAA 4096 CCAUGCAACUGUCCAUCAC 4097 GUGAUGGACAGUUGCAUGG 4098 CAUGCAACUGUCCAUCACG 4099 CGUGAUGGACAGUUGCAUG 4100 AUGCAACUGUCCAUCACGG 4101 CCGUGAUGGACAGUUGCAU 4102 UGCAACUGUCCAUCACGGC 4103 GCCGUGAUGGACAGUUGCA 4104 GCAACUGUCCAUCACGGCU 4105 AGCCGUGAUGGACAGUUGC 4106 CAACUGUCCAUCACGGCUG 4107 CAGCCGUGAUGGACAGUUG 4108 AACUGUCCAUCACGGCUGC 4109 GCAGCCGUGAUGGACAGUU 4110 ACUGUCCAUCACGGCUGCA 4111 UGCAGCCGUGAUGGACAGU 4112 CUGUCCAUCACGGCUGCAA 4113 UUGCAGCCGUGAUGGACAG 4114 UGUCCAUCACGGCUGCAAC 4115 GUUGCAGCCGUGAUGGACA 4116 GUCCAUCACGGCUGCAACU 4117 AGUUGCAGCCGUGAUGGAC 4118 UCCAUCACGGCUGCAACUG 4119 CAGUUGCAGCCGUGAUGGA 4120 CCAUCACGGCUGCAACUGA 4121 UCAGUUGCAGCCGUGAUGG 4122 CAUCACGGCUGCAACUGAA 4123 UUCAGUUGCAGCCGUGAUG 4124 ACAGCGCACCAGAAGCUAA 4125 UUAGCUUCUGGUGCGCUGU 4126 CAGCGCACCAGAAGCUAAA 4127 UUUAGCUUCUGGUGCGCUG 4128 AGCGCACCAGAAGCUAAAG 4129 CUUUAGCUUCUGGUGCGCU 4130 GCGCACCAGAAGCUAAAGU 4131 ACUUUAGCUUCUGGUGCGC 4132 CGCACCAGAAGCUAAAGUC 4133 GACUUUAGCUUCUGGUGCG 4134 GCACCAGAAGCUAAAGUCU 4135 AGACUUUAGCUUCUGGUGC 4136 CACCAGAAGCUAAAGUCUU 4137 AAGACUUUAGCUUCUGGUG 4138 ACCAGAAGCUAAAGUCUUG 4139 CAAGACUUUAGCUUCUGGU 4140 CCAGAAGCUAAAGUCUUGA 4141 UCAAGACUUUAGCUUCUGG 4142 CAGAAGCUAAAGUCUUGAU 4143 AUCAAGACUUUAGCUUCUG 4144 AGAAGCUAAAGUCUUGAUG 4145 CAUCAAGACUUUAGCUUCU 4146 GAAGCUAAAGUCUUGAUGC 4147 GCAUCAAGACUUUAGCUUC 4148 AAGCUAAAGUCUUGAUGCC 4149 GGCAUCAAGACUUUAGCUU 4150 AGCUAAAGUCUUGAUGCCA 4151 UGGCAUCAAGACUUUAGCU 4152 CCCAUUCACAUCUCUGUCA 4153 UGACAGAGAUGUGAAUGGG 4154 UUCACAUCUCUGUCACGUC 4155 GACGUGACAGAGAUGUGAA 4156 UCACAUCUCUGUCACGUCC 4157 GGACGUGACAGAGAUGUGA 4158 CACAUCUCUGUCACGUCCA 4159 UGGACGUGACAGAGAUGUG 4160 UCUCUGUCACGUCCACUAA 4161 UUAGUGGACGUGACAGAGA 4162 CUCUGUCACGUCCACUAAU 4163 AUUAGUGGACGUGACAGAG 4164 UCUGUCACGUCCACUAAUC 4165 GAUUAGUGGACGUGACAGA 4166 CUGUCACGUCCACUAAUCG 4167 CGAUUAGUGGACGUGACAG 4168 UGUCACGUCCACUAAUCGG 4169 CCGAUUAGUGGACGUGACA 4170 GUCACGUCCACUAAUCGGC 4171 GCCGAUUAGUGGACGUGAC 4172 UCACGUCCACUAAUCGGCA 4173 UGCCGAUUAGUGGACGUGA 4174 CACGUCCACUAAUCGGCAA 4175 UUGCCGAUUAGUGGACGUG 4176 ACGUCCACUAAUCGGCAAA 4177 UUUGCCGAUUAGUGGACGU 4178 CGUCCACUAAUCGGCAAAA 4179 UUUUGCCGAUUAGUGGACG 4180 GUCCACUAAUCGGCAAAAG 4181 CUUUUGCCGAUUAGUGGAC 4182 UCCACUAAUCGGCAAAAGG 4183 CCUUUUGCCGAUUAGUGGA 4184 CCACUAAUCGGCAAAAGGA 4185 UCCUUUUGCCGAUUAGUGG 4186 CACUAAUCGGCAAAAGGAG 4187 CUCCUUUUGCCGAUUAGUG 4188 AGAAGAUGACCUAAGUGUG 4189 CACACUUAGGUCAUCUUCU 4190 GAAGAUGACCUAAGUGUGA 4191 UCACACUUAGGUCAUCUUC 4192 AAGAUGACCUAAGUGUGAC 4193 GUCACACUUAGGUCAUCUU 4194 AGAUGACCUAAGUGUGACU 4195 AGUCACACUUAGGUCAUCU 4196 GAUGACCUAAGUGUGACUG 4197 CAGUCACACUUAGGUCAUC 4198 AUGACCUAAGUGUGACUGC 4199 GCAGUCACACUUAGGUCAU 4200 UGACCUAAGUGUGACUGCA 4201 UGCAGUCACACUUAGGUCA 4202 AAAAUGAAGCCAGAGCAGU 4203 ACUGCUCUGGCUUCAUUUU 4204 UCCGACCAAGGAGGAAGGA 4205 UCCUUCCUCCUUGGUCGGA 4206 CCGACCAAGGAGGAAGGAA 4207 UUCCUUCCUCCUUGGUCGG 4208 AGAGCAGGUAAGCAGGAAG 4209 CUUCCUGCUUACCUGCUCU 4210 GAGCAGGUAAGCAGGAAGG 4211 CCUUCCUGCUUACCUGCUC 4212 AGGUAAGCAGGAAGGCCAG 4213 CUGGCCUUCCUGCUUACCU 4214 AGCAGGAAGGCCAGUGUCC 4215 GGACACUGGCCUUCCUGCU 4216 CAGGAAGGCCAGUGUCCCA 4217 UGGGACACUGGCCUUCCUG 4218 UCCCAGACAGGACCCUAAU 4219 AUUAGGGUCCUGUCUGGGA 4220 CCCAGACAGGACCCUAAUG 4221 CAUUAGGGUCCUGUCUGGG 4222 CCAGACAGGACCCUAAUGA 4223 UCAUUAGGGUCCUGUCUGG 4224 CAGACAGGACCCUAAUGAU 4225 AUCAUUAGGGUCCUGUCUG 4226 AGACAGGACCCUAAUGAUC 4227 GAUCAUUAGGGUCCUGUCU 4228 GACAGGACCCUAAUGAUCC 4229 GGAUCAUUAGGGUCCUGUC 4230 GGACCCUAAUGAUCCUGAA 4231 UUCAGGAUCAUUAGGGUCC 4232 CCUAAUGAUCCUGAAUCCA 4233 UGGAUUCAGGAUCAUUAGG 4234 CUAAUGAUCCUGAAUCCAU 4235 AUGGAUUCAGGAUCAUUAG 4236 UGAUCCUGAAUCCAUGUAU 4237 AUACAUGGAUUCAGGAUCA 4238 GAUCCUGAAUCCAUGUAUC 4239 GAUACAUGGAUUCAGGAUC 4240 AUCCUGAAUCCAUGUAUCA 4241 UGAUACAUGGAUUCAGGAU 4242 UCCAUGUAUCAGGAUCCAU 4243 AUGGAUCCUGAUACAUGGA 4244 CCAUGUAUCAGGAUCCAUC 4245 GAUGGAUCCUGAUACAUGG 4246 CAUGUAUCAGGAUCCAUCC 4247 GGAUGGAUCCUGAUACAUG 4248 UCACCUCUCAUUUUCCAAA 4249 UUUGGAAAAUGAGAGGUGA 4250 UCCAAAGCCCUGCCAUGCU 4251 AGCAUGGCAGGGCUUUGGA 4252 CCAAAGCCCUGCCAUGCUG 4253 CAGCAUGGCAGGGCUUUGG 4254 CAUGCUGCCAUCCCACUUC 4255 GAAGUGGGAUGGCAGCAUG 4256 AUGCUGCCAUCCCACUUCC 4257 GGAAGUGGGAUGGCAGCAU 4258 UGCUGCCAUCCCACUUCCC 4259 GGGAAGUGGGAUGGCAGCA 4260 CGGGUUCCCUUUUCCUAAA 4261 UUUAGGAAAAGGGAACCCG 4262 AGCUGCAGCUUAUGGCUUC 4263 GAAGCCAUAAGCUGCAGCU 4264 GCUGCAGCUUAUGGCUUCU 4265 AGAAGCCAUAAGCUGCAGC 4266 CUGCAGCUUAUGGCUUCUC 4267 GAGAAGCCAUAAGCUGCAG 4268 UGCAGCUUAUGGCUUCUCC 4269 GGAGAAGCCAUAAGCUGCA 4270 GCAGCUUAUGGCUUCUCCA 4271 UGGAGAAGCCAUAAGCUGC 4272 CAGCUUAUGGCUUCUCCAG 4273 CUGGAGAAGCCAUAAGCUG 4274 AGCUUAUGGCUUCUCCAGU 4275 ACUGGAGAAGCCAUAAGCU 4276 GCUUAUGGCUUCUCCAGUA 4277 UACUGGAGAAGCCAUAAGC 4278 CUUAUGGCUUCUCCAGUAG 4279 CUACUGGAGAAGCCAUAAG 4280 UUAUGGCUUCUCCAGUAGG 4281 CCUACUGGAGAAGCCAUAA 4282 UAUGGCUUCUCCAGUAGGU 4283 ACCUACUGGAGAAGCCAUA 4284 AUGGCUUCUCCAGUAGGUG 4285 CACCUACUGGAGAAGCCAU 4286 UGGCUUCUCCAGUAGGUGG 4287 CCACCUACUGGAGAAGCCA 4288 GGCUUCUCCAGUAGGUGGC 4289 GCCACCUACUGGAGAAGCC 4290 GCUUCUCCAGUAGGUGGCA 4291 UGCCACCUACUGGAGAAGC 4292 CUUCUCCAGUAGGUGGCAG 4293 CUGCCACCUACUGGAGAAG 4294 UUCUCCAGUAGGUGGCAGC 4295 GCUGCCACCUACUGGAGAA 4296 UCUCCAGUAGGUGGCAGCA 4297 UGCUGCCACCUACUGGAGA 4298 CUCCAGUAGGUGGCAGCAC 4299 GUGCUGCCACCUACUGGAG 4300 ACACCAGAAGUCACAUUUC 4301 GAAAUGUGACUUCUGGUGU 4302 GAAGUCACAUUUCAUCCUU 4303 AAGGAUGAAAUGUGACUUC 4304 AAGUCACAUUUCAUCCUUU 4305 AAAGGAUGAAAUGUGACUU 4306 AGUCACAUUUCAUCCUUUU 4307 AAAAGGAUGAAAUGUGACU 4308 UUUCAUCCUUUUACAUGGU 4309 ACCAUGUAAAAGGAUGAAA 4310 UUCAUCCUUUUACAUGGUU 4311 AACCAUGUAAAAGGAUGAA 4312 UCAUCCUUUUACAUGGUUC 4313 GAACCAUGUAAAAGGAUGA 4314 CAUCCUUUUACAUGGUUCC 4315 GGAACCAUGUAAAAGGAUG 4316 UGGUUCCCAUCUACCCUCA 4317 UGAGGGUAGAUGGGAACCA 4318 GGUUCCCAUCUACCCUCAC 4319 GUGAGGGUAGAUGGGAACC 4320 GUUCCCAUCUACCCUCACA 4321 UGUGAGGGUAGAUGGGAAC 4322 GGCAAUUCUUCCUCCAGGA 4323 UCCUGGAGGAAGAAUUGCC 4324 GCAAUUCUUCCUCCAGGAC 4325 GUCCUGGAGGAAGAAUUGC 4326 CAAUUCUUCCUCCAGGACC 4327 GGUCCUGGAGGAAGAAUUG 4328 AAUUCUUCCUCCAGGACCC 4329 GGGUCCUGGAGGAAGAAUU 4330 CCCUUGGACUUUGCCCUUC 4331 GAAGGGCAAAGUCCAAGGG 4332 CCUUGGACUUUGCCCUUCU 4333 AGAAGGGCAAAGUCCAAGG 4334 CUUGGACUUUGCCCUUCUU 4335 AAGAAGGGCAAAGUCCAAG 4336 UUGGACUUUGCCCUUCUUA 4337 UAAGAAGGGCAAAGUCCAA 4338 UGGACUUUGCCCUUCUUAC 4339 GUAAGAAGGGCAAAGUCCA 4340 GGACUUUGCCCUUCUUACU 4341 AGUAAGAAGGGCAAAGUCC 4342 UUUGCCCUUCUUACUGGCC 4343 GGCCAGUAAGAAGGGCAAA 4344 UUGCCCUUCUUACUGGCCA 4345 UGGCCAGUAAGAAGGGCAA 4346 UGCCCUUCUUACUGGCCAG 4347 CUGGCCAGUAAGAAGGGCA 4348 UCUUACUGGCCAGGCAGGG 4349 CCCUGCCUGGCCAGUAAGA 4350 GGCCAGAGUCCAGGCUUGA 4351 UCAAGCCUGGACUCUGGCC 4352 GCCAGAGUCCAGGCUUGAC 4353 GUCAAGCCUGGACUCUGGC 4354 GUCCAGGCUUGACUCAUUC 4355 GAAUGAGUCAAGCCUGGAC 4356 AGGCUUGACUCAUUCCCAC 4357 GUGGGAAUGAGUCAAGCCU 4358 GACUCAUUCCCACCUUGUC 4359 GACAAGGUGGGAAUGAGUC 4360 ACUCAUUCCCACCUUGUCC 4361 GGACAAGGUGGGAAUGAGU 4362 UCAUUCCCACCUUGUCCUG 4363 CAGGACAAGGUGGGAAUGA 4364 CACCUUGUCCUGGGCUGAG 4365 CUCAGCCCAGGACAAGGUG 4366 ACCACCCAGCCCAGAAGUU 4367 AACUUCUGGGCUGGGUGGU 4368 CCACCCAGCCCAGAAGUUC 4369 GAACUUCUGGGCUGGGUGG 4370 CACCCAGCCCAGAAGUUCC 4371 GGAACUUCUGGGCUGGGUG 4372 ACCCAGCCCAGAAGUUCCA 4373 UGGAACUUCUGGGCUGGGU 4374 CCAGAAGUUCCAGGGAAGG 4375 CCUUCCCUGGAACUUCUGG 4376 CAGAAGUUCCAGGGAAGGA 4377 UCCUUCCCUGGAACUUCUG 4378 AACUCUCCGGUCCACCAUG 4379 CAUGGUGGACCGGAGAGUU 4380 ACUCUCCGGUCCACCAUGG 4381 CCAUGGUGGACCGGAGAGU 4382 CACCAUGGAGUACCUCUCA 4383 UGAGAGGUACUCCAUGGUG 4384 ACCAUGGAGUACCUCUCAG 4385 CUGAGAGGUACUCCAUGGU 4386 UGGAGUACCUCUCAGCUCU 4387 AGAGCUGAGAGGUACUCCA 4388 GGAGUACCUCUCAGCUCUG 4389 CAGAGCUGAGAGGUACUCC 4390 GAGUACCUCUCAGCUCUGA 4391 UCAGAGCUGAGAGGUACUC 4392 AGUACCUCUCAGCUCUGAA 4393 UUCAGAGCUGAGAGGUACU 4394 CCAGUGACUUACUCAGGUG 4395 CACCUGAGUAAGUCACUGG 4396 CAGUGACUUACUCAGGUGA 4397 UCACCUGAGUAAGUCACUG 4398 AGUGACUUACUCAGGUGAC 4399 GUCACCUGAGUAAGUCACU 4400 GUGACUUACUCAGGUGACU 4401 AGUCACCUGAGUAAGUCAC 4402 UGACUUACUCAGGUGACUG 4403 CAGUCACCUGAGUAAGUCA 4404 GACUUACUCAGGUGACUGC 4405 GCAGUCACCUGAGUAAGUC 4406 ACUUACUCAGGUGACUGCU 4407 AGCAGUCACCUGAGUAAGU 4408 CUUACUCAGGUGACUGCUA 4409 UAGCAGUCACCUGAGUAAG 4410 UUACUCAGGUGACUGCUAA 4411 UUAGCAGUCACCUGAGUAA 4412 UACUCAGGUGACUGCUAAC 4413 GUUAGCAGUCACCUGAGUA 4414 ACUCAGGUGACUGCUAACC 4415 GGUUAGCAGUCACCUGAGU 4416 CUCAGGUGACUGCUAACCC 4417 GGGUUAGCAGUCACCUGAG 4418 GGUGACUGCUAACCCUCCG 4419 CGGAGGGUUAGCAGUCACC 4420 GUGACUGCUAACCCUCCGC 4421 GCGGAGGGUUAGCAGUCAC 4422 UGACUGCUAACCCUCCGCU 4423 AGCGGAGGGUUAGCAGUCA 4424 GACUGCUAACCCUCCGCUC 4425 GAGCGGAGGGUUAGCAGUC 4426 ACUGCUAACCCUCCGCUCU 4427 AGAGCGGAGGGUUAGCAGU 4428 CUGCUAACCCUCCGCUCUA 4429 UAGAGCGGAGGGUUAGCAG 4430 UGCUAACCCUCCGCUCUAC 4431 GUAGAGCGGAGGGUUAGCA 4432 AACCCUCCGCUCUACCCUC 4433 GAGGGUAGAGCGGAGGGUU 4434 ACUCCACAGUGGGCUUGUC 4435 GACAAGCCCACUGUGGAGU 4436 CUCCACAGUGGGCUUGUCA 4437 UGACAAGCCCACUGUGGAG 4438 UCCACAGUGGGCUUGUCAA 4439 UUGACAAGCCCACUGUGGA 4440 CCACAGUGGGCUUGUCAAG 4441 CUUGACAAGCCCACUGUGG 4442 GUCAAGCUCCUGAGCCACC 4443 GGUGGCUCAGGAGCUUGAC 4444 CCAUGGUCUCUCCCUCAUC 4445 GAUGAGGGAGAGACCAUGG 4446 CAUGGUCUCUCCCUCAUCC 4447 GGAUGAGGGAGAGACCAUG 4448 AUGGUCUCUCCCUCAUCCC 4449 GGGAUGAGGGAGAGACCAU 4450 UCUCUCCCUCAUCCCUAAU 4451 AUUAGGGAUGAGGGAGAGA 4452 CUCUCCCUCAUCCCUAAUC 4453 GAUUAGGGAUGAGGGAGAG 4454 UCUCCCUCAUCCCUAAUCG 4455 CGAUUAGGGAUGAGGGAGA 4456 CUCCCUCAUCCCUAAUCGA 4457 UCGAUUAGGGAUGAGGGAG 4458 UCCCUCAUCCCUAAUCGAU 4459 AUCGAUUAGGGAUGAGGGA 4460 CCCUCAUCCCUAAUCGAUA 4461 UAUCGAUUAGGGAUGAGGG 4462 CCUCAUCCCUAAUCGAUAA 4463 UUAUCGAUUAGGGAUGAGG 4464 CUCAUCCCUAAUCGAUAAA 4465 UUUAUCGAUUAGGGAUGAG 4466 AACCUAGAUCUCUCCCUCC 4467 GGAGGGAGAGAUCUAGGUU 4468 ACCUAGAUCUCUCCCUCCC 4469 GGGAGGGAGAGAUCUAGGU 4470 CUAGAUCUCUCCCUCCCUA 4471 UAGGGAGGGAGAGAUCUAG 4472 UAGAUCUCUCCCUCCCUAG 4473 CUAGGGAGGGAGAGAUCUA 4474 AGAUCUCUCCCUCCCUAGC 4475 GCUAGGGAGGGAGAGAUCU 4476 GAUCUCUCCCUCCCUAGCC 4477 GGCUAGGGAGGGAGAGAUC 4478 AUCUCUCCCUCCCUAGCCC 4479 GGGCUAGGGAGGGAGAGAU 4480 UAGCCCUCUAGCCACUCUA 4481 UAGAGUGGCUAGAGGGCUA 4482 AGCCCUCUAGCCACUCUAC 4483 GUAGAGUGGCUAGAGGGCU 4484 CUCUAGCCACUCUACCCUC 4485 GAGGGUAGAGUGGCUAGAG 4486 UCUAGCCACUCUACCCUCA 4487 UGAGGGUAGAGUGGCUAGA 4488 CUAGCCACUCUACCCUCAU 4489 AUGAGGGUAGAGUGGCUAG 4490 UAGCCACUCUACCCUCAUC 4491 GAUGAGGGUAGAGUGGCUA 4492 AGCCACUCUACCCUCAUCA 4493 UGAUGAGGGUAGAGUGGCU 4494 GCCACUCUACCCUCAUCAU 4495 AUGAUGAGGGUAGAGUGGC 4496 CCACUCUACCCUCAUCAUG 4497 CAUGAUGAGGGUAGAGUGG 4498 CACUCUACCCUCAUCAUGC 4499 GCAUGAUGAGGGUAGAGUG 4500 ACUCUACCCUCAUCAUGCC 4501 GGCAUGAUGAGGGUAGAGU 4502 CUCUACCCUCAUCAUGCCC 4503 GGGCAUGAUGAGGGUAGAG 4504 UCUACCCUCAUCAUGCCCU 4505 AGGGCAUGAUGAGGGUAGA 4506 CUACCCUCAUCAUGCCCUU 4507 AAGGGCAUGAUGAGGGUAG 4508 UACCCUCAUCAUGCCCUUU 4509 AAAGGGCAUGAUGAGGGUA 4510 ACCCUCAUCAUGCCCUUUA 4511 UAAAGGGCAUGAUGAGGGU 4512 CCCUCAUCAUGCCCUUUAC 4513 GUAAAGGGCAUGAUGAGGG 4514 CUCAUCAUGCCCUUUACAC 4515 GUGUAAAGGGCAUGAUGAG 4516 UCAUCAUGCCCUUUACACU 4517 AGUGUAAAGGGCAUGAUGA 4518 CCCUUCUUGACUUUUCUUC 4519 GAAGAAAAGUCAAGAAGGG 4520 CUUCUUGACUUUUCUUCUC 4521 GAGAAGAAAAGUCAAGAAG 4522 GACUUUUCUUCUCAACUAC 4523 GUAGUUGAGAAGAAAAGUC 4524 ACUUUUCUUCUCAACUACC 4525 GGUAGUUGAGAAGAAAAGU 4526 CUUUUCUUCUCAACUACCA 4527 UGGUAGUUGAGAAGAAAAG 4528 UUUUCUUCUCAACUACCAG 4529 CUGGUAGUUGAGAAGAAAA 4530 UAUCUAAUAUAAGCUCGGA 4531 UCCGAGCUUAUAUUAGAUA 4532 AUCUAAUAUAAGCUCGGAG 4533 CUCCGAGCUUAUAUUAGAU 4534 UCUAAUAUAAGCUCGGAGU 4535 ACUCCGAGCUUAUAUUAGA 4536 CUAAUAUAAGCUCGGAGUU 4537 AACUCCGAGCUUAUAUUAG 4538 UAAUAUAAGCUCGGAGUUU 4539 AAACUCCGAGCUUAUAUUA 4540 AAUAUAAGCUCGGAGUUUG 4541 CAAACUCCGAGCUUAUAUU 4542 AUAUAAGCUCGGAGUUUGG 4543 CCAAACUCCGAGCUUAUAU 4544 UAUAAGCUCGGAGUUUGGA 4545 UCCAAACUCCGAGCUUAUA 4546 AUAAGCUCGGAGUUUGGAC 4547 GUCCAAACUCCGAGCUUAU 4548 UAAGCUCGGAGUUUGGACG 4549 CGUCCAAACUCCGAGCUUA 4550 AAGCUCGGAGUUUGGACGG 4551 CCGUCCAAACUCCGAGCUU 4552 AGCUCGGAGUUUGGACGGA 4553 UCCGUCCAAACUCCGAGCU 4554 GCUCGGAGUUUGGACGGAG 4555 CUCCGUCCAAACUCCGAGC 4556 CUCGGAGUUUGGACGGAGG 4557 CCUCCGUCCAAACUCCGAG 4558 UCGGAGUUUGGACGGAGGG 4559 CCCUCCGUCCAAACUCCGA 4560 CGGAGUUUGGACGGAGGGU 4561 ACCCUCCGUCCAAACUCCG 4562 UUUGGACGGAGGGUCUGGA 4563 UCCAGACCCUCCGUCCAAA 4564 CCCAGCGACCUUUCCGUGU 4565 ACACGGAAAGGUCGCUGGG 4566 CCAGCGACCUUUCCGUGUC 4567 GACACGGAAAGGUCGCUGG 4568 CAGCGACCUUUCCGUGUCU 4569 AGACACGGAAAGGUCGCUG 4570 AGCGACCUUUCCGUGUCUG 4571 CAGACACGGAAAGGUCGCU 4572 GCGACCUUUCCGUGUCUGU 4573 ACAGACACGGAAAGGUCGC 4574 CGACCUUUCCGUGUCUGUG 4575 CACAGACACGGAAAGGUCG 4576 CUUUCCGUGUCUGUGAUCA 4577 UGAUCACAGACACGGAAAG 4578 UUUCCGUGUCUGUGAUCAC 4579 GUGAUCACAGACACGGAAA 4580 UUCCGUGUCUGUGAUCACA 4581 UGUGAUCACAGACACGGAA 4582 AAGGCCUGACAGCUGCCAC 4583 GUGGCAGCUGUCAGGCCUU 4584 GCCAGGAGCUGCUAGCCAA 4585 UUGGCUAGCAGCUCCUGGC 4586 CCAGGAGCUGCUAGCCAAA 4587 UUUGGCUAGCAGCUCCUGG 4588 GAGCUGCUAGCCAAAGUAA 4589 UUACUUUGGCUAGCAGCUC 4590 AGCUGCUAGCCAAAGUAAG 4591 CUUACUUUGGCUAGCAGCU 4592 GCUGCUAGCCAAAGUAAGU 4593 ACUUACUUUGGCUAGCAGC 4594 CUGCUAGCCAAAGUAAGUA 4595 UACUUACUUUGGCUAGCAG 4596 UGCUAGCCAAAGUAAGUAG 4597 CUACUUACUUUGGCUAGCA 4598 GCUAGCCAAAGUAAGUAGG 4599 CCUACUUACUUUGGCUAGC 4600 UAGCCAAAGUAAGUAGGCC 4601 GGCCUACUUACUUUGGCUA 4602 AGCCAAAGUAAGUAGGCCA 4603 UGGCCUACUUACUUUGGCU 4604 GCCAAAGUAAGUAGGCCAA 4605 UUGGCCUACUUACUUUGGC 4606 CCAAAGUAAGUAGGCCAAG 4607 CUUGGCCUACUUACUUUGG 4608 CAAAGUAAGUAGGCCAAGU 4609 ACUUGGCCUACUUACUUUG 4610 AAAGUAAGUAGGCCAAGUU 4611 AACUUGGCCUACUUACUUU 4612 AAGUAAGUAGGCCAAGUUC 4613 GAACUUGGCCUACUUACUU 4614 AGUAAGUAGGCCAAGUUCC 4615 GGAACUUGGCCUACUUACU 4616 GUAAGUAGGCCAAGUUCCU 4617 AGGAACUUGGCCUACUUAC 4618 UAAGUAGGCCAAGUUCCUC 4619 GAGGAACUUGGCCUACUUA 4620 UAGGCCAAGUUCCUCGGUU 4621 AACCGAGGAACUUGGCCUA 4622 AGGCCAAGUUCCUCGGUUC 4623 GAACCGAGGAACUUGGCCU 4624 GGCCAAGUUCCUCGGUUCC 4625 GGAACCGAGGAACUUGGCC 4626 GCCAAGUUCCUCGGUUCCU 4627 AGGAACCGAGGAACUUGGC 4628 CCAAGUUCCUCGGUUCCUA 4629 UAGGAACCGAGGAACUUGG 4630 CAAGUUCCUCGGUUCCUAU 4631 AUAGGAACCGAGGAACUUG 4632 AAGUUCCUCGGUUCCUAUA 4633 UAUAGGAACCGAGGAACUU 4634 AGUUCCUCGGUUCCUAUAG 4635 CUAUAGGAACCGAGGAACU 4636 GUUCCUCGGUUCCUAUAGC 4637 GCUAUAGGAACCGAGGAAC 4638 UUCCUCGGUUCCUAUAGCA 4639 UGCUAUAGGAACCGAGGAA 4640 UCCUCGGUUCCUAUAGCAG 4641 CUGCUAUAGGAACCGAGGA 4642 CAGUGGCAACUUGUGAUGA 4643 UCAUCACAAGUUGCCACUG 4644 AGUGGCAACUUGUGAUGAU 4645 AUCAUCACAAGUUGCCACU 4646 GUGGCAACUUGUGAUGAUG 4647 CAUCAUCACAAGUUGCCAC 4648 GGCAACUUGUGAUGAUGGA 4649 UCCAUCAUCACAAGUUGCC 4650 ACUUGUGAUGAUGGAGCAG 4651 CUGCUCCAUCAUCACAAGU 4652 CUUGUGAUGAUGGAGCAGA 4663 UCUGCUCCAUCAUCACAAG 4654 GUGAUGAUGGAGCAGAGGG 4666 CCCUCUGCUCCAUCAUCAC 4656 UGAUGAUGGAGCAGAGGGC 4667 GCCCUCUGCUCCAUCAUCA 4658 UGGAGCAGAGGGCUGAAGU 4659 ACUUCAGCCCUCUGCUCCA 4660 GGAGCAGAGGGCUGAAGUC 4661 GACUUCAGCCCUCUGCUCC 4662 GAGCAGAGGGCUGAAGUCA 4663 UGACUUCAGCCCUCUGCUC 4664 CUAAAAGCAGCGGAGUGGG 4665 CCCACUCCGCUGCUUUUAG 4666 UAAAAGCAGCGGAGUGGGC 4667 GCCCACUCCGCUGCUUUUA 4668 AAAAGCAGCGGAGUGGGCC 4669 GGCCCACUCCGCUGCUUUU 4670 AAAGCAGCGGAGUGGGCCU 4671 AGGCCCACUCCGCUGCUUU 4672 AAGCAGCGGAGUGGGCCUA 4673 UAGGCCCACUCCGCUGCUU 4674 AGCAGCGGAGUGGGCCUAA 4675 UUAGGCCCACUCCGCUGCU 4676 GCAGCGGAGUGGGCCUAAU 4677 AUUAGGCCCACUCCGCUGC 4678 CAGCGGAGUGGGCCUAAUG 4679 CAUUAGGCCCACUCCGCUG 4680 AGCGGAGUGGGCCUAAUGA 4681 UCAUUAGGCCCACUCCGCU 4682 GCGGAGUGGGCCUAAUGAG 4683 CUCAUUAGGCCCACUCCGC 4684 AGUGGGCCUAAUGAGCUCU 4685 AGAGCUCAUUAGGCCCACU 4686 GUGGGCCUAAUGAGCUCUG 4687 CAGAGCUCAUUAGGCCCAC 4688 UGGGCCUAAUGAGCUCUGG 4689 CCAGAGCUCAUUAGGCCCA 4690 GGGCCUAAUGAGCUCUGGU 4691 ACCAGAGCUCAUUAGGCCC 4692 GGCCUAAUGAGCUCUGGUC 4693 GACCAGAGCUCAUUAGGCC 4694 GCCUAAUGAGCUCUGGUCA 4695 UGACCAGAGCUCAUUAGGC 4696 CCUAAUGAGCUCUGGUCAA 4697 UUGACCAGAGCUCAUUAGG 4698 CUAAUGAGCUCUGGUCAAU 4699 AUUGACCAGAGCUCAUUAG 4700 UAAUGAGCUCUGGUCAAUU 4701 AAUUGACCAGAGCUCAUUA 4702 AAUGAGCUCUGGUCAAUUU 4703 AAAUUGACCAGAGCUCAUU 4704 AUGAGCUCUGGUCAAUUUG 4705 CAAAUUGACCAGAGCUCAU 4706 UGAGCUCUGGUCAAUUUGU 4707 ACAAAUUGACCAGAGCUCA 4708 CUGGUCAAUUUGUUCAUUU 4709 AAAUGAACAAAUUGACCAG 4710 CAAUUUGUUCAUUUUCCAC 4711 GUGGAAAAUGAACAAAUUG 4712 AGUGAGCUUUUCUAUGGGA 4713 UCCCAUAGAAAAGCUCACU 4714 AGCUUUUCUAUGGGAGCAG 4715 CUGCUCCCAUAGAAAAGCU 4716 GAAUUCAGAAGCUAGUAUG 4717 CAUACUAGCUUCUGAAUUC 4718 AUUCAGAAGCUAGUAUGGA 4719 UCCAUACUAGCUUCUGAAU 4720 UUCAGAAGCUAGUAUGGAA 4721 UUCCAUACUAGCUUCUGAA 4722 AAAGGUGAUUUGUGUGACA 4728 UGUCACACAAAUCACCUUU 4724 AUUCUGAUUCUGCCACUUC 4725 GAAGUGGCAGAAUCAGAAU 4726 AUUCUGCCACUUCCUGCCU 4727 AGGCAGGAAGUGGCAGAAU 4728 GCCACUUCCUGCCUGUCAA 4729 UUGACAGGCAGGAAGUGGC 4730 CCACUUCCUGCCUGUCAAA 4731 UUUGACAGGCAGGAAGUGG 4732 AACCUUGGGAAGUUGUUCA 4733 UGAACAACUUCCCAAGGUU 4734 ACCUUGGGAAGUUGUUCAA 4735 UUGAACAACUUCCCAAGGU 4736 CCUUGGGAAGUUGUUCAAC 4737 GUUGAACAACUUCCCAAGG 4738 GGGAAGUUGUUCAACCUAC 4739 GUAGGUUGAACAACUUCCC 4740 GGAAGUUGUUCAACCUACC 4741 GGUAGGUUGAACAACUUCC 4742 GAAGUUGUUCAACCUACCA 4743 UGGUAGGUUGAACAACUUC 4744 AAGUUGUUCAACCUACCAA 4745 UUGGUAGGUUGAACAACUU 4746 AGUUGUUCAACCUACCAAA 4747 UUUGGUAGGUUGAACAACU 4748 GUUGUUCAACCUACCAAAA 4749 UUUUGGUAGGUUGAACAAC 4750 GCAAUAAUAAUACAUCACC 4751 GGUGAUGUAUUAUUAUUGC 4752 AUAAUAAUACAUCACCUCC 4753 GGAGGUGAUGUAUUAUUAU 4754 UAAUACAUCACCUCCUAGG 4755 CCUAGGAGGUGAUGUAUUA 4756 AAUACAUCACCUCCUAGGG 4757 CCCUAGGAGGUGAUGUAUU 4758 AUACAUCACCUCCUAGGGU 4759 ACCCUAGGAGGUGAUGUAU 4760 UACAUCACCUCCUAGGGUU 4761 AACCCUAGGAGGUGAUGUA 4762 ACAUCACCUCCUAGGGUUG 4763 CAACCCUAGGAGGUGAUGU 4764 AAAGGAGUAAGAGGAUAAU 4765 AUUAUCCUCUUACUCCUUU 4766 AAGGAGUAAGAGGAUAAUG 4767 CAUUAUCCUCUUACUCCUU 4768 AGUAAGAGGAUAAUGUAGG 4769 CCUACAUUAUCCUCUUACU 4770 GUAAGAGGAUAAUGUAGGU 4771 ACCUACAUUAUCCUCUUAC 4772 UAAGAGGAUAAUGUAGGUA 4778 UACCUACAUUAUCCUCUUA 4774 AAGAGGAUAAUGUAGGUAA 4776 UUACCUACAUUAUCCUCUU 4776 AGAGGAUAAUGUAGGUAAA 4777 UUUACCUACAUUAUCCUCU 4778 GAGGAUAAUGUAGGUAAAG 4779 CUUUACCUACAUUAUCCUC 4780 GGAUAAUGUAGGUAAAGUC 4781 GACUUUACCUACAUUAUCC 4782 AUAAUGUAGGUAAAGUCCU 4783 AGGACUUUACCUACAUUAU 4784 GUAGGUAAAGUCCUCAUAC 4785 GUAUGAGGACUUUACCUAC 4786 GUAAAGUCCUCAUACCUGG 4787 CCAGGUAUGAGGACUUUAC 4788 UAAAGUCCUCAUACCUGGC 4789 GCCAGGUAUGAGGACUUUA 4790 AAAGUCCUCAUACCUGGCA 4791 UGCCAGGUAUGAGGACUUU 4792 AAGUCCUCAUACCUGGCAC 4793 GUGCCAGGUAUGAGGACUU 4794 AGUCCUCAUACCUGGCACA 4795 UGUGCCAGGUAUGAGGACU 4796 GUCCUCAUACCUGGCACAG 4797 CUGUGCCAGGUAUGAGGAC 4798 UCCUCAUACCUGGCACAGA 4799 UCUGUGCCAGGUAUGAGGA 4800 UCUUGAGGGUGUGGGAAGU 4801 ACUUCCCACACCCUCAAGA 4802 CUUGAGGGUGUGGGAAGUG 4803 CACUUCCCACACCCUCAAG 4804 UUGAGGGUGUGGGAAGUGA 4805 UCACUUCCCACACCCUCAA 4806 UGAGGGUGUGGGAAGUGAG 4807 CUCACUUCCCACACCCUCA 4808 AGGGUGUGGGAAGUGAGGU 4809 ACCUCACUUCCCACACCCU 4810 GGGUGUGGGAAGUGAGGUG 4811 CACCUCACUUCCCACACCC 4812 GGGAAGUGAGGUGCAGCAU 4813 AUGCUGCACCUCACUUCCC 4814 GGAAGUGAGGUGCAGCAUU 4815 AAUGCUGCACCUCACUUCC 4816 GAAGUGAGGUGCAGCAUUG 4817 CAAUGCUGCACCUCACUUC 4818 AAGUGAGGUGCAGCAUUGU 4819 ACAAUGCUGCACCUCACUU 4820 AGUGAGGUGCAGCAUUGUA 4821 UACAAUGCUGCACCUCACU 4822 GUGAGGUGCAGCAUUGUAG 4823 CUACAAUGCUGCACCUCAC 4824 UGAGGUGCAGCAUUGUAGA 4825 UCUACAAUGCUGCACCUCA 4826 GAGGUGCAGCAUUGUAGAU 4827 AUCUACAAUGCUGCACCUC 4828 AGGUGCAGCAUUGUAGAUA 4829 UAUCUACAAUGCUGCACCU 4830 GGUGCAGCAUUGUAGAUAA 4831 UUAUCUACAAUGCUGCACC 4832 GUGCAGCAUUGUAGAUAAG 4833 CUUAUCUACAAUGCUGCAC 4834 UGCAGCAUUGUAGAUAAGA 4835 UCUUAUCUACAAUGCUGCA 4836 GCAUUGUAGAUAAGACAGA 4837 UCUGUCUUAUCUACAAUGC 4838 CAUUGUAGAUAAGACAGAA 4839 UUCUGUCUUAUCUACAAUG 4840 AUUGUAGAUAAGACAGAAG 4841 CUUCUGUCUUAUCUACAAU 4842 AUAAGACAGAAGGGUGGAC 4843 GUCCACCCUUCUGUCUUAU 4844 UAAGACAGAAGGGUGGACU 4845 AGUCCACCCUUCUGUCUUA 4846 AACCUGGCUUGCUUUCCAA 4847 UUGGAAAGCAAGCCAGGUU 4848 CCUGGCUUGCUUUCCAAUU 4849 AAUUGGAAAGCAAGCCAGG 4850 ACCAGAAGUGACUUGGAGG 4851 CCUCCAAGUCACUUCUGGU 4852 CCAGAAGUGACUUGGAGGG 4853 CCCUCCAAGUCACUUCUGG 4854 AGAUGCCAAUGACAUGGUA 4855 UACCAUGUCAUUGGCAUCU 4856 GAUGCCAAUGACAUGGUAG 4857 CUACCAUGUCAUUGGCAUC 4858 AUGCCAAUGACAUGGUAGG 4859 CCUACCAUGUCAUUGGCAU 4860 CAAUGACAUGGUAGGAGCA 4861 UGCUCCUACCAUGUCAUUG 4862 AAUGACAUGGUAGGAGCAA 4863 UUGCUCCUACCAUGUCAUU 4864 AUGACAUGGUAGGAGCAAA 4865 UUUGCUCCUACCAUGUCAU 4866 UGACAUGGUAGGAGCAAAG 4867 CUUUGCUCCUACCAUGUCA 4868 GACAUGGUAGGAGCAAAGA 4869 UCUUUGCUCCUACCAUGUC 4870 AAAAGGUCAGCCUCUAGCU 4871 AGCUAGAGGCUGACCUUUU 4872 AAAGGUCAGCCUCUAGCUA 4873 UAGCUAGAGGCUGACCUUU 4874 AGGUCAGCCUCUAGCUAGG 4875 CCUAGCUAGAGGCUGACCU 4876 GGUCAGCCUCUAGCUAGGA 4877 UCCUAGCUAGAGGCUGACC 4878 GUCAGCCUCUAGCUAGGAU 4879 AUCCUAGCUAGAGGCUGAC 4880 CAGCCUCUAGCUAGGAUCC 4881 GGAUCCUAGCUAGAGGCUG 4882 AGCCUCUAGCUAGGAUCCC 4883 GGGAUCCUAGCUAGAGGCU 4884 AGAGCUGCAACCUUUAGGA 4885 UCCUAAAGGUUGCAGCUCU 4886 GAGCUGCAACCUUUAGGAG 4887 CUCCUAAAGGUUGCAGCUC 4888 AGCUGCAACCUUUAGGAGG 4889 CCUCCUAAAGGUUGCAGCU 4890 UUUAGGAGGUAUCAAAGUG 4891 CACUUUGAUACCUCCUAAA 4892 UUAGGAGGUAUCAAAGUGC 4893 GCACUUUGAUACCUCCUAA 4894 UAGGAGGUAUCAAAGUGCC 4895 GGCACUUUGAUACCUCCUA 4896 GUCAAAGUGGGACAUCGAC 4897 GUCGAUGUCCCACUUUGAC 4898 CAUCGACCAAUGUCUAGAG 4899 CUCUAGACAUUGGUCGAUG 4900 AUCGACCAAUGUCUAGAGC 4901 GCUCUAGACAUUGGUCGAU 4902 ACCAAUGUCUAGAGCCAAC 4903 GUUGGCUCUAGACAUUGGU 4904 CAAUGUCUAGAGCCAACUG 4905 CAGUUGGCUCUAGACAUUG 4906 AAUGUCUAGAGCCAACUGA 4907 UCAGUUGGCUCUAGACAUU 4908 AUGUCUAGAGCCAACUGAU 4909 AUCAGUUGGCUCUAGACAU 4910 UGUCUAGAGCCAACUGAUG 4911 CAUCAGUUGGCUCUAGACA 4912 GUCUAGAGCCAACUGAUGG 4913 CCAUCAGUUGGCUCUAGAC 4914 UCUAGAGCCAACUGAUGGA 4915 UCCAUCAGUUGGCUCUAGA 4916 CUAGAGCCAACUGAUGGAU 4917 AUCCAUCAGUUGGCUCUAG 4918 UAGAGCCAACUGAUGGAUG 4919 CAUCCAUCAGUUGGCUCUA 4920 AGAGCCAACUGAUGGAUGU 4921 ACAUCCAUCAGUUGGCUCU 4922 GAGCCAACUGAUGGAUGUU 4923 AACAUCCAUCAGUUGGCUC 4924 AACUGAUGGAUGUUGGGCA 4925 UGCCCAACAUCCAUCAGUU 4926 UGGAUGUUGGGCAGCUAAA 4927 UUUAGCUGCCCAACAUCCA 4928 GGAUGUUGGGCAGCUAAAG 4929 CUUUAGCUGCCCAACAUCC 4930 GAUGUUGGGCAGCUAAAGA 4931 UCUUUAGCUGCCCAACAUC 4932 UUGGGCAGCUAAAGAGGGA 4933 UCCCUCUUUAGCUGCCCAA 4934 UGGGCAGCUAAAGAGGGAA 4935 UUCCCUCUUUAGCUGCCCA 4936 GGGCAGCUAAAGAGGGAAG 4937 CUUCCCUCUUUAGCUGCCC 4938 GGCAGCUAAAGAGGGAAGG 4939 CCUUCCCUCUUUAGCUGCC 4940 GCAGCUAAAGAGGGAAGGG 4941 CCCUUCCCUCUUUAGCUGC 4942 GGGCAUGGGAUAAGACCUG 4943 CAGGUCUUAUCCCAUGCCC 4944 GGCAUGGGAUAAGACCUGC 4945 GCAGGUCUUAUCCCAUGCC 4946 GCAUGGGAUAAGACCUGCC 4947 GGCAGGUCUUAUCCCAUGC 4948 CAUGGGAUAAGACCUGCCC 4949 GGGCAGGUCUUAUCCCAUG 4950 AUGGGAUAAGACCUGCCCU 4951 AGGGCAGGUCUUAUCCCAU 4952 UGGGAUAAGACCUGCCCUU 4953 AAGGGCAGGUCUUAUCCCA 4954 GGGAUAAGACCUGCCCUUC 4955 GAAGGGCAGGUCUUAUCCC 4956 GGAUAAGACCUGCCCUUCU 4957 AGAAGGGCAGGUCUUAUCC 4958 AGACCUGCCCUUCUUGCUU 4959 AAGCAAGAAGGGCAGGUCU 4960 GACCUGCCCUUCUUGCUUC 4961 GAAGCAAGAAGGGCAGGUC 4962 CCUGCCCUUCUUGCUUCUU 4963 AAGAAGCAAGAAGGGCAGG 4964 CUGCCCUUCUUGCUUCUUG 4965 CAAGAAGCAAGAAGGGCAG 4966 UGCCCUUCUUGCUUCUUGC 4967 GCAAGAAGCAAGAAGGGCA 4968 UCUUGCUUCUUGCCAUUGG 4969 CCAAUGGCAAGAAGCAAGA 4970 CUUGCUUCUUGCCAUUGGG 4971 CCCAAUGGCAAGAAGCAAG 4972 UUGCUUCUUGCCAUUGGGC 4973 GCCCAAUGGCAAGAAGCAA 4974 CCAUUGGGCAGGCAUUGGA 4975 UCCAAUGCCUGCCCAAUGG 4976 CAUUGGGCAGGCAUUGGAG 4977 CUCCAAUGCCUGCCCAAUG 4978 GACCCUACUGCUGAAUGGA 4979 UCCAUUCAGCAGUAGGGUC 4980 UACUGCUGAAUGGAGUGCU 4981 AGCACUCCAUUCAGCAGUA 4982 ACUGCUGAAUGGAGUGCUA 4983 UAGCACUCCAUUCAGCAGU 4984 CUGCUGAAUGGAGUGCUAA 4985 UUAGCACUCCAUUCAGCAG 4986 UGCUGAAUGGAGUGCUAAC 4987 GUUAGCACUCCAUUCAGCA 4988 GCUGAAUGGAGUGCUAACC 4989 GGUUAGCACUCCAUUCAGC 4990 CUGAAUGGAGUGCUAACCC 4991 GGGUUAGCACUCCAUUCAG 4992 UAACCCUGGUGCUAGAGGA 4993 UCCUCUAGCACCAGGGUUA 4994 AACCCUGGUGCUAGAGGAG 4995 CUCCUCUAGCACCAGGGUU 4996 ACCCUGGUGCUAGAGGAGG 4997 CCUCCUCUAGCACCAGGGU 4998 CCCUGGUGCUAGAGGAGGA 4999 UCCUCCUCUAGCACCAGGG 5000 CCUGGUGCUAGAGGAGGAU 5001 AUCCUCCUCUAGCACCAGG 5002 CUGGUGCUAGAGGAGGAUG 5003 CAUCCUCCUCUAGCACCAG 5004 GGUGCUAGAGGAGGAUGGA 5005 UCCAUCCUCCUCUAGCACC 5006 GUGCUAGAGGAGGAUGGAA 5007 UUCCAUCCUCCUCUAGCAC 5008 CUGCAGUGGACAGUGAGGA 5009 UCCUCACUGUCCACUGCAG 5010 UGCAGUGGACAGUGAGGAC 5011 GUCCUCACUGUCCACUGCA 5012 GCAGUGGACAGUGAGGACU 5013 AGUCCUCACUGUCCACUGC 5014 CAGUGGACAGUGAGGACUU 5015 AAGUCCUCACUGUCCACUG 5016 AGUGGACAGUGAGGACUUC 5017 GAAGUCCUCACUGUCCACU 5018 GUGGACAGUGAGGACUUCU 5019 AGAAGUCCUCACUGUCCAC 5020 UGGACAGUGAGGACUUCUU 5021 AAGAAGUCCUCACUGUCCA 5022 GGACAGUGAGGACUUCUUC 5023 GAAGAAGUCCUCACUGUCC 5024 AGUGAGGACUUCUUCCAGC 5025 GCUGGAAGAAGUCCUCACU 5026 GUGAGGACUUCUUCCAGCU 5027 AGCUGGAAGAAGUCCUCAC 5028 UGAGGACUUCUUCCAGCUG 5029 CAGCUGGAAGAAGUCCUCA 5030 GAGGACUUCUUCCAGCUGC 5031 GCAGCUGGAAGAAGUCCUC 5032 GUGCCUGAUGGUGUUGCAG 5033 CUGCAACACCAUCAGGCAC 5034 GAUGGUGUUGCAGUCUGGU 5035 ACCAGACUGCAACACCAUC 5036 UGGUGUUGCAGUCUGGUCA 5037 UGACCAGACUGCAACACCA 5038 GGUGUUGCAGUCUGGUCAG 5039 CUGACCAGACUGCAACACC 5040 GUGUUGCAGUCUGGUCAGA 5041 UCUGACCAGACUGCAACAC 5042 UGCAGUCUGGUCAGAGCUG 5043 CAGCUCUGACCAGACUGCA 5044 GCAGUCUGGUCAGAGCUGG 5045 CCAGCUCUGACCAGACUGC 5046 CAGUCUGGUCAGAGCUGGA 5047 UCCAGCUCUGACCAGACUG 5048 AGUCUGGUCAGAGCUGGAG 5049 CUCCAGCUCUGACCAGACU 5050 GUCUGGUCAGAGCUGGAGC 5051 GCUCCAGCUCUGACCAGAC 5052 UCUGGUCAGAGCUGGAGCC 5053 GGCUCCAGCUCUGACCAGA 5054 UGGUCAGAGCUGGAGCCCU 5055 AGGGCUCCAGCUCUGACCA 5056 GGUCAGAGCUGGAGCCCUA 5057 UAGGGCUCCAGCUCUGACC 5058 GUCAGAGCUGGAGCCCUAC 5059 GUAGGGCUCCAGCUCUGAC 5060 CAAGGGUAAGAGGCCUAUA 5061 UAUAGGCCUCUUACCCUUG 5062 AAGGGUAAGAGGCCUAUAC 5063 GUAUAGGCCUCUUACCCUU 5064 AGGGUAAGAGGCCUAUACU 5065 AGUAUAGGCCUCUUACCCU 5066 GGGUAAGAGGCCUAUACUG 5067 CAGUAUAGGCCUCUUACCC 5068 GGUAAGAGGCCUAUACUGG 5069 CCAGUAUAGGCCUCUUACC 5070 GUAAGAGGCCUAUACUGGG 5071 CCCAGUAUAGGCCUCUUAC 5072 GGGCUGCUUCCAAUGCCUG 5073 CAGGCAUUGGAAGCAGCCC 5074 GGCUGCUUCCAAUGCCUGU 5075 ACAGGCAUUGGAAGCAGCC 5076 GCUGCUUCCAAUGCCUGUC 5077 GACAGGCAUUGGAAGCAGC 5078 CUGCUUCCAAUGCCUGUCC 5079 GGACAGGCAUUGGAAGCAG 5080 UGCUUCCAAUGCCUGUCCU 5081 AGGACAGGCAUUGGAAGCA 5082 GCUUCCAAUGCCUGUCCUU 5083 AAGGACAGGCAUUGGAAGC 5084 CUUCCAAUGCCUGUCCUUU 5085 AAAGGACAGGCAUUGGAAG 5086 UUCCAAUGCCUGUCCUUUA 5087 UAAAGGACAGGCAUUGGAA 5088 UCCAAUGCCUGUCCUUUAG 5089 CUAAAGGACAGGCAUUGGA 5090 CAAUGCCUGUCCUUUAGAG 5091 CUCUAAAGGACAGGCAUUG 5092 AAUGCCUGUCCUUUAGAGC 5093 GCUCUAAAGGACAGGCAUU 5094 AUGCCUGUCCUUUAGAGCU 5095 AGCUCUAAAGGACAGGCAU 5096 CUUCCUCUCUAGCUUAACC 5097 GGUUAAGCUAGAGAGGAAG 5098 UUCCUCUCUAGCUUAACCC 5099 GGGUUAAGCUAGAGAGGAA 5100 UCUCUAGCUUAACCCUGAU 5101 AUCAGGGUUAAGCUAGAGA 5102 UAGCUUAACCCUGAUCCUG 5103 CAGGAUCAGGGUUAAGCUA 5104 GACCAGGUGCAGGAGGAGU 5105 ACUCCUCCUGCACCUGGUC 5106 ACCAGGUGCAGGAGGAGUU 5107 AACUCCUCCUGCACCUGGU 5108 CCAGGUGCAGGAGGAGUUG 5109 CAACUCCUCCUGCACCUGG 5110 CAGGUGCAGGAGGAGUUGU 5111 ACAACUCCUCCUGCACCUG 5112 AGGUGCAGGAGGAGUUGUG 5113 CACAACUCCUCCUGCACCU 5114 UGCAGGAGGAGUUGUGGAA 5115 UUCCACAACUCCUCCUGCA 5116 GCAGGAGGAGUUGUGGAAU 5117 AUUCCACAACUCCUCCUGC 5118 AGGAGGAGUUGUGGAAUUG 5119 CAAUUCCACAACUCCUCCU 5120 GGAGGAGUUGUGGAAUUGU 5121 ACAAUUCCACAACUCCUCC 5122 GAGGAGUUGUGGAAUUGUC 5123 GACAAUUCCACAACUCCUC 5124 AGGAGUUGUGGAAUUGUCA 5125 UGACAAUUCCACAACUCCU 5126 GGAGUUGUGGAAUUGUCAA 5127 UUGACAAUUCCACAACUCC 5128 GAGUUGUGGAAUUGUCAAG 5129 CUUGACAAUUCCACAACUC 5130 AGUUGUGGAAUUGUCAAGG 5131 CCUUGACAAUUCCACAACU 5132 GUUGUGGAAUUGUCAAGGA 5133 UCCUUGACAAUUCCACAAC 5134 UGGAAUUGUCAAGGAUGUC 5135 GACAUCCUUGACAAUUCCA 5136 GGAAUUGUCAAGGAUGUCA 5137 UGACAUCCUUGACAAUUCC 5138 AGUCCAAGCGAGGGAGGGU 5139 ACCCUCCCUCGCUUGGACU 5140 CAAGCGAGGGAGGGUCUGA 5141 UCAGACCCUCCCUCGCUUG 5142 AAGCGAGGGAGGGUCUGAC 5143 GUCAGACCCUCCCUCGCUU 5144 CUGACCCAGUGCUGAUGGA 5145 UCCAUCAGCACUGGGUCAG 5146 AGAUUAGUGGUGGGUGUCU 5147 AGACACCCACCACUAAUCU 5148 AUUAGUGGUGGGUGUCUGG 5149 CCAGACACCCACCACUAAU 5150 UUAGUGGUGGGUGUCUGGU 5151 ACCAGACACCCACCACUAA 5152 UAGUGGUGGGUGUCUGGUA 5153 UACCAGACACCCACCACUA 5154 AGUGGUGGGUGUCUGGUAU 5155 AUACCAGACACCCACCACU 5156 GUGGUGGGUGUCUGGUAUG 5157 CAUACCAGACACCCACCAC 5158 UGGUGGGUGUCUGGUAUGA 5159 UCAUACCAGACACCCACCA 5160 GGUGGGUGUCUGGUAUGAG 5161 CUCAUACCAGACACCCACC 5162 GUGGGUGUCUGGUAUGAGG 5163 CCUCAUACCAGACACCCAC 5164 UGGGUGUCUGGUAUGAGGA 5165 UCCUCAUACCAGACACCCA 5166 GGGUGUCUGGUAUGAGGAU 5167 AUCCUCAUACCAGACACCC 5168 GGUGUCUGGUAUGAGGAUC 5169 GAUCCUCAUACCAGACACC 5170 GUGUCUGGUAUGAGGAUCU 5171 AGAUCCUCAUACCAGACAC 5172 UGUCUGGUAUGAGGAUCUA 5173 UAGAUCCUCAUACCAGACA 5174 CAAGGGUGUCCUACAGAGU 5175 ACUCUGUAGGACACCCUUG 5176 AAGGGUGUCCUACAGAGUG 5177 CACUCUGUAGGACACCCUU 5178 AGGGUGUCCUACAGAGUGG 5179 CCACUCUGUAGGACACCCU 5180 GGGUGUCCUACAGAGUGGA 5181 UCCACUCUGUAGGACACCC 5182 GGUGUCCUACAGAGUGGAG 5183 CUCCACUCUGUAGGACACC 5184 UCCUACAGAGUGGAGUGCU 5185 AGCACUCCACUCUGUAGGA 5186 AGUGGAGUGCUGUCAUAUG 5187 CAUAUGACAGCACUCCACU 5188 GUGGAGUGCUGUCAUAUGG 5189 CCAUAUGACAGCACUCCAC 5190 UGGAGUGCUGUCAUAUGGC 5191 GCCAUAUGACAGCACUCCA 5192 GGAGUGCUGUCAUAUGGCC 5193 GGCCAUAUGACAGCACUCC 5194 GAGUGCUGUCAUAUGGCCU 5195 AGGCCAUAUGACAGCACUC 5196 AGUGCUGUCAUAUGGCCUG 5197 CAGGCCAUAUGACAGCACU 5198 GUGCUGUCAUAUGGCCUGG 5199 CCAGGCCAUAUGACAGCAC 5200 UGCUGUCAUAUGGCCUGGG 5201 CCCAGGCCAUAUGACAGCA 5202 GCUGUCAUAUGGCCUGGGA 5203 UCCCAGGCCAUAUGACAGC 5204 CUGUCAUAUGGCCUGGGAC 5205 GUCCCAGGCCAUAUGACAG 5206 UGUCAUAUGGCCUGGGACG 5207 CGUCCCAGGCCAUAUGACA 5208 GUCAUAUGGCCUGGGACGG 5209 CCGUCCCAGGCCAUAUGAC 5210 AGAGGCCCAAGCACAGCAA 5211 UUGCUGUGCUUGGGCCUCU 5212 GAGGCCCAAGCACAGCAAG 5213 CUUGCUGUGCUUGGGCCUC 5214 AGGCCCAAGCACAGCAAGG 5215 CCUUGCUGUGCUUGGGCCU 5216 GGCCCAAGCACAGCAAGGA 5217 UCCUUGCUGUGCUUGGGCC 5218 CCAAGCACAGCAAGGACAU 5219 AUGUCCUUGCUGUGCUUGG 5220 GCCCGAUUCACCUUUGACG 5221 CGUCAAAGGUGAAUCGGGC 5222 GAUUCACCUUUGACGUGUA 5223 UACACGUCAAAGGUGAAUC 5224 AUUCACCUUUGACGUGUAC 5225 GUACACGUCAAAGGUGAAU 5226 UUGGCAGCCUGAAUGUCAA 5227 UUGACAUUCAGGCUGCCAA 5228 UGGCAGCCUGAAUGUCAAA 5229 UUUGACAUUCAGGCUGCCA 5230 GGCAGCCUGAAUGUCAAAG 5231 CUUUGACAUUCAGGCUGCC 5232 GCAGCCUGAAUGUCAAAGC 5233 GCUUUGACAUUCAGGCUGC 5234 CAGCCUGAAUGUCAAAGCC 5235 GGCUUUGACAUUCAGGCUG 5236 AGCCUGAAUGUCAAAGCCA 5237 UGGCUUUGACAUUCAGGCU 5238 GCCUGAAUGUCAAAGCCAC 5239 GUGGCUUUGACAUUCAGGC 5240 GUCAAAGCCACAUUCUACG 5241 CGUAGAAUGUGGCUUUGAC 5242 UCAAAGCCACAUUCUACGG 5243 CCGUAGAAUGUGGCUUUGA 5244 CAAAGCCACAUUCUACGGG 5245 CCCGUAGAAUGUGGCUUUG 5246 AAAGCCACAUUCUACGGGC 5247 GCCCGUAGAAUGUGGCUUU 5248 GCCACAUUCUACGGGCUCU 5249 AGAGCCCGUAGAAUGUGGC 5250 CCACAUUCUACGGGCUCUA 5251 UAGAGCCCGUAGAAUGUGG 5252 CACAUUCUACGGGCUCUAC 5253 GUAGAGCCCGUAGAAUGUG 5254 UUCUACGGGCUCUACUCUA 5255 UAGAGUAGAGCCCGUAGAA 5256 UCUACGGGCUCUACUCUAU 5257 AUAGAGUAGAGCCCGUAGA 5258 CUACGGGCUCUACUCUAUG 5259 CAUAGAGUAGAGCCCGUAG 5260 CUCUAUGAGUUGUGACUUU 5261 AAAGUCACAACUCAUAGAG 5262 UCUAUGAGUUGUGACUUUC 5263 GAAAGUCACAACUCAUAGA 5264 UGAGUUGUGACUUUCAAGG 5265 CCUUGAAAGUCACAACUCA 5266 GAGUUGUGACUUUCAAGGA 5267 UCCUUGAAAGUCACAACUC 5268 AGUUGUGACUUUCAAGGAC 5269 GUCCUUGAAAGUCACAACU 5270 GUUGUGACUUUCAAGGACU 5271 AGUCCUUGAAAGUCACAAC 5272 GACUUUCAAGGACUUGGCC 5273 GGCCAAGUCCUUGAAAGUC 5274 UUUCAAGGACUUGGCCCAA 5275 UUGGGCCAAGUCCUUGAAA 5276 UUCAAGGACUUGGCCCAAA 5277 UUUGGGCCAAGUCCUUGAA 5278 CCCUACAGUUGGAUAGUCC 5279 GGACUAUCCAACUGUAGGG 5280 CCUACAGUUGGAUAGUCCC 5281 GGGACUAUCCAACUGUAGG 5282 AUUCGUCCUCUUGCACCCA 5283 UGGGUGCAAGAGGACGAAU 5284 UUCGUCCUCUUGCACCCAC 5285 GUGGGUGCAAGAGGACGAA 5286 UCCUCUUGCACCCACCUAC 5287 GUAGGUGGGUGCAAGAGGA 5288 CCUCUUGCACCCACCUACC 5289 GGUAGGUGGGUGCAAGAGG 5290 CUCUUGCACCCACCUACCC 5291 GGGUAGGUGGGUGCAAGAG 5292 CUAGUUAGCUCUUGCUUGU 5293 ACAAGCAAGAGCUAACUAG 5294 UAGUUAGCUCUUGCUUGUG 5295 CACAAGCAAGAGCUAACUA 5296 AGUUAGCUCUUGCUUGUGG 5297 CCACAAGCAAGAGCUAACU 5298 UUAGCUCUUGCUUGUGGAA 5299 UUCCACAAGCAAGAGCUAA 5300 UCCUCAUCUCCCAGCUUGA 5301 UCAAGCUGGGAGAUGAGGA 5302 AUCUCCCAGCUUGAUGGCU 5303 AGCCAUCAAGCUGGGAGAU 5304 UCUCCCAGCUUGAUGGCUU 5305 AAGCCAUCAAGCUGGGAGA 5306 CUCCCAGCUUGAUGGCUUC 5307 GAAGCCAUCAAGCUGGGAG 5308 UCCCAGCUUGAUGGCUUCC 5309 GGAAGCCAUCAAGCUGGGA 5310 CCCAGCUUGAUGGCUUCCU 5311 AGGAAGCCAUCAAGCUGGG 5312 CCAGCUUGAUGGCUUCCUC 5313 GAGGAAGCCAUCAAGCUGG 5314 UGAUGGCUUCCUCCCAAGU 5315 ACUUGGGAGGAAGCCAUCA 5316 GAUGGCUUCCUCCCAAGUU 5317 AACUUGGGAGGAAGCCAUC 5318 GGCUUCCUCCCAAGUUUUC 5319 GAAAACUUGGGAGGAAGCC 5320 CCUCCCAAGUUUUCCAAAU 5321 AUUUGGAAAACUUGGGAGG 5322 CCCAAGUUUUCCAAAUCAU 5323 AUGAUUUGGAAAACUUGGG 5324 CCAAGUUUUCCAAAUCAUC 5325 GAUGAUUUGGAAAACUUGG 5326 CAAGUUUUCCAAAUCAUCU 5327 AGAUGAUUUGGAAAACUUG 5328 AAGUUUUCCAAAUCAUCUG 5329 CAGAUGAUUUGGAAAACUU 5330 GUUUUCCAAAUCAUCUGAU 5331 AUCAGAUGAUUUGGAAAAC 5332 AUCUGAUUUCCUCUUGUCU 5333 AGACAAGAGGAAAUCAGAU 5334 UCUGAUUUCCUCUUGUCUC 5335 GAGACAAGAGGAAAUCAGA 5336 CUGAUUUCCUCUUGUCUCU 5337 AGAGACAAGAGGAAAUCAG 5338 CUCUUGUCUCUGCCAUUCA 5339 UGAAUGGCAGAGACAAGAG 5340 GUUGGACCUCCACACUGCU 5341 AGCAGUGUGGAGGUCCAAC 5342 CCACACUGCUGCAAGGCCU 5343 AGGCCUUGCAGCAGUGUGG 5344 CACACUGCUGCAAGGCCUG 5345 CAGGCCUUGCAGCAGUGUG 5346 ACACUGCUGCAAGGCCUGG 5347 CCAGGCCUUGCAGCAGUGU 5348 UGCAAGGCCUGGGCCAUAU 5349 AUAUGGCCCAGGCCUUGCA 5350 GCAAGGCCUGGGCCAUAUG 5351 CAUAUGGCCCAGGCCUUGC 5352 CAAGGCCUGGGCCAUAUGU 5353 ACAUAUGGCCCAGGCCUUG 5354 AAGGCCUGGGCCAUAUGUU 5355 AACAUAUGGCCCAGGCCUU 5356 AGGCCUGGGCCAUAUGUUG 5357 CAACAUAUGGCCCAGGCCU 5358 GGCCUGGGCCAUAUGUUGC 5359 GCAACAUAUGGCCCAGGCC 5360 GCCUGGGCCAUAUGUUGCU 5361 AGCAACAUAUGGCCCAGGC 5362 CCUGGGCCAUAUGUUGCUG 5363 CAGCAACAUAUGGCCCAGG 5364 GGCCAUAUGUUGCUGGGAA 5365 UUCCCAGCAACAUAUGGCC 5366 CCAUAUGUUGCUGGGAAUU 5367 AAUUCCCAGCAACAUAUGG 5368 GGAAUUUCCUCCACCCUUC 5369 GAAGGGUGGAGGAAAUUCC 5370 GAAUUUCCUCCACCCUUCG 5371 CGAAGGGUGGAGGAAAUUC 5372 AAUUUCCUCCACCCUUCGU 5373 ACGAAGGGUGGAGGAAAUU 5374 AUUUCCUCCACCCUUCGUC 5375 GACGAAGGGUGGAGGAAAU 5376 UUUCCUCCACCCUUCGUCA 5377 UGACGAAGGGUGGAGGAAA 5378 UUCCUCCACCCUUCGUCAU 5379 AUGACGAAGGGUGGAGGAA 5380 UCCUCCACCCUUCGUCAUG 5381 CAUGACGAAGGGUGGAGGA 5382 CCUCCACCCUUCGUCAUGC 5383 GCAUGACGAAGGGUGGAGG 5384 CUCCACCCUUCGUCAUGCA 5385 UGCAUGACGAAGGGUGGAG 5386 CCUUCGUCAUGCAGUGGAG 5387 CUCCACUGCAUGACGAAGG 5388 CUUCGUCAUGCAGUGGAGG 5389 CCUCCACUGCAUGACGAAG 5390 UUCGUCAUGCAGUGGAGGG 5391 CCCUCCACUGCAUGACGAA 5392 CGCCUCCAUUCCUACUAAG 5393 CUUAGUAGGAAUGGAGGCG 5394 GCCUCCAUUCCUACUAAGG 5395 CCUUAGUAGGAAUGGAGGC 5396 CCUCCAUUCCUACUAAGGG 5397 CCCUUAGUAGGAAUGGAGG 5398 CAGAAUCAUUCCAACCGAC 5399 GUCGGUUGGAAUGAUUCUG 5400 AGAAUCAUUCCAACCGACC 5401 GGUCGGUUGGAAUGAUUCU 5402 GAAUCAUUCCAACCGACCC 5403 GGGUCGGUUGGAAUGAUUC 5404 AAUCAUUCCAACCGACCCA 5405 UGGGUCGGUUGGAAUGAUU 5406 AUCAUUCCAACCGACCCAC 5407 GUGGGUCGGUUGGAAUGAU 5408 UCAUUCCAACCGACCCACU 5409 AGUGGGUCGGUUGGAAUGA 5410 UCCAACCGACCCACUGCAA 5411 UUGCAGUGGGUCGGUUGGA 5412 CCAACCGACCCACUGCAAA 5413 UUUGCAGUGGGUCGGUUGG 5414 CAACCGACCCACUGCAAAG 5415 CUUUGCAGUGGGUCGGUUG 5416 AACCGACCCACUGCAAAGA 5417 UCUUUGCAGUGGGUCGGUU 5418 ACCGACCCACUGCAAAGAC 5419 GUCUUUGCAGUGGGUCGGU 5420 CCGACCCACUGCAAAGACU 5421 AGUCUUUGCAGUGGGUCGG 5422 CGACCCACUGCAAAGACUA 5423 UAGUCUUUGCAGUGGGUCG 5424 GACCCACUGCAAAGACUAU 5425 AUAGUCUUUGCAGUGGGUC 5426 ACCCACUGCAAAGACUAUG 5427 CAUAGUCUUUGCAGUGGGU 5428 ACUGCAAAGACUAUGACAG 5429 CUGUCAUAGUCUUUGCAGU 5430 CUGCAAAGACUAUGACAGC 5431 GCUGUCAUAGUCUUUGCAG 5432 UGCAAAGACUAUGACAGCA 5433 UGCUGUCAUAGUCUUUGCA 5434 GCAAAGACUAUGACAGCAU 5435 AUGCUGUCAUAGUCUUUGC 5436 AAAGACUAUGACAGCAUCA 5437 UGAUGCUGUCAUAGUCUUU 5438 AAGACUAUGACAGCAUCAA 5439 UUGAUGCUGUCAUAGUCUU 5440 AGACUAUGACAGCAUCAAA 5441 UUUGAUGCUGUCAUAGUCU 5442 GACUAUGACAGCAUCAAAU 5443 AUUUGAUGCUGUCAUAGUC 5444 CUAUGACAGCAUCAAAUUU 5445 AAAUUUGAUGCUGUCAUAG 5446 UAUGACAGCAUCAAAUUUC 5447 GAAAUUUGAUGCUGUCAUA 5448 GCAUCAAAUUUCAGGACCU 5449 AGGUCCUGAAAUUUGAUGC 5450 AUCAAAUUUCAGGACCUGC 5451 GCAGGUCCUGAAAUUUGAU 5452 UCAAAUUUCAGGACCUGCA 5453 UGCAGGUCCUGAAAUUUGA 5454 UUCAGGACCUGCAGACAGU 5455 ACUGUCUGCAGGUCCUGAA 5456 UCAGGACCUGCAGACAGUA 5457 UACUGUCUGCAGGUCCUGA 5458 CAGGACCUGCAGACAGUAC 5459 GUACUGUCUGCAGGUCCUG 5460 AGGACCUGCAGACAGUACA 5461 UGUACUGUCUGCAGGUCCU 5462 GGACCUGCAGACAGUACAG 5463 CUGUACUGUCUGCAGGUCC 5464 CUGCAGACAGUACAGGCUA 5465 UAGCCUGUACUGUCUGCAG 5466 GACAGUACAGGCUAGAUAA 5467 UUAUCUAGCCUGUACUGUC 5468 ACAGUACAGGCUAGAUAAC 5469 GUUAUCUAGCCUGUACUGU 5470 CAGUACAGGCUAGAUAACC 5471 GGUUAUCUAGCCUGUACUG 5472 AGUACAGGCUAGAUAACCC 5473 GGGUUAUCUAGCCUGUACU 5474 GUACAGGCUAGAUAACCCA 5475 UGGGUUAUCUAGCCUGUAC 5476 UACAGGCUAGAUAACCCAC 5477 GUGGGUUAUCUAGCCUGUA 5478 GCUAGAUAACCCACCCAAU 5479 AUUGGGUGGGUUAUCUAGC 5480 CUAGAUAACCCACCCAAUU 5481 AAUUGGGUGGGUUAUCUAG 5482 AGAUAACCCACCCAAUUUC 5483 GAAAUUGGGUGGGUUAUCU 5484 GAUAACCCACCCAAUUUCC 5485 GGAAAUUGGGUGGGUUAUC 5486 AACCUUUCAGCAUAACGCC 5487 GGCGUUAUGCUGAAAGGUU 5488 ACCUUUCAGCAUAACGCCU 5489 AGGCGUUAUGCUGAAAGGU 5490 CCUUUCAGCAUAACGCCUC 5491 GAGGCGUUAUGCUGAAAGG 5492 CUUUCAGCAUAACGCCUCA 5493 UGAGGCGUUAUGCUGAAAG 5494 UUUCAGCAUAACGCCUCAC 5495 GUGAGGCGUUAUGCUGAAA 5496 UUCAGCAUAACGCCUCACA 5497 UGUGAGGCGUUAUGCUGAA 5498 UCAGCAUAACGCCUCACAU 5499 AUGUGAGGCGUUAUGCUGA 5500 CAGCAUAACGCCUCACAUC 5501 GAUGUGAGGCGUUAUGCUG 5502 AGCAUAACGCCUCACAUCC 5503 GGAUGUGAGGCGUUAUGCU 5504 GCAUAACGCCUCACAUCCC 5505 GGGAUGUGAGGCGUUAUGC 5506 AACGCCUCACAUCCCAAGU 5507 ACUUGGGAUGUGAGGCGUU 5508 ACGCCUCACAUCCCAAGUC 5509 GACUUGGGAUGUGAGGCGU 5510 CGCCUCACAUCCCAAGUCU 5511 AGACUUGGGAUGUGAGGCG 5512 UCACAUCCCAAGUCUAUAC 5513 GUAUAGACUUGGGAUGUGA 5514 CACAUCCCAAGUCUAUACC 5515 GGUAUAGACUUGGGAUGUG 5516 ACAUCCCAAGUCUAUACCC 5517 GGGUAUAGACUUGGGAUGU 5518 CAUCCCAAGUCUAUACCCU 5519 AGGGUAUAGACUUGGGAUG 5520 AAUGCUGUUCUUUCCUAGC 5521 GCUAGGAAAGAACAGCAUU 5522 AUGCUGUUCUUUCCUAGCC 5523 GGCUAGGAAAGAACAGCAU 5524 CUGUUCUUUCCUAGCCACC 5525 GGUGGCUAGGAAAGAACAG 5526 UGUUCUUUCCUAGCCACCU 5527 AGGUGGCUAGGAAAGAACA 5528 GCCAAGAUCAAGAUGUCCC 5529 GGGACAUCUUGAUCUUGGC 5530 UCUUGAUCCCAGCCUGACU 5531 AGUCAGGCUGGGAUCAAGA 5532 CUUGAUCCCAGCCUGACUG 5533 CAGUCAGGCUGGGAUCAAG 5534 UUGAUCCCAGCCUGACUGC 5535 GCAGUCAGGCUGGGAUCAA 5536 UGAUCCCAGCCUGACUGCU 5537 AGCAGUCAGGCUGGGAUCA 5538 CUGACUGCUGCUACAUCUA 5539 UAGAUGUAGCAGCAGUCAG 5540 GACUGCUGCUACAUCUAAU 5541 AUUAGAUGUAGCAGCAGUC 5542 ACUGCUGCUACAUCUAAUC 5543 GAUUAGAUGUAGCAGCAGU 5544 CUGCUGCUACAUCUAAUCC 5545 GGAUUAGAUGUAGCAGCAG 5546 UGCUGCUACAUCUAAUCCC 5547 GGGAUUAGAUGUAGCAGCA 5548 CCUACCAAUGCCUCCUGUC 5549 GACAGGAGGCAUUGGUAGG 5550 CUACCAAUGCCUCCUGUCC 5551 GGACAGGAGGCAUUGGUAG 5552 CCAAUGCCUCCUGUCCCUA 5553 UAGGGACAGGAGGCAUUGG 5554 CAAUGCCUCCUGUCCCUAA 5555 UUAGGGACAGGAGGCAUUG 5556 AAUGCCUCCUGUCCCUAAA 5557 UUUAGGGACAGGAGGCAUU 5558 CCCAGCAUACUGAUGACAG 5559 CUGUCAUCAGUAUGCUGGG 5560 CCAGCAUACUGAUGACAGC 5561 GCUGUCAUCAGUAUGCUGG 5562 CAUACUGAUGACAGCCCUC 5563 GAGGGCUGUCAUCAGUAUG 5564 AUACUGAUGACAGCCCUCU 5565 AGAGGGCUGUCAUCAGUAU 5566 UACUGAUGACAGCCCUCUC 5567 GAGAGGGCUGUCAUCAGUA 5568 ACUGAUGACAGCCCUCUCU 5569 AGAGAGGGCUGUCAUCAGU 5570 CUGAUGACAGCCCUCUCUG 5571 CAGAGAGGGCUGUCAUCAG 5572 UGAUGACAGCCCUCUCUGA 5573 UCAGAGAGGGCUGUCAUCA 5574 GAUGACAGCCCUCUCUGAC 5575 GUCAGAGAGGGCUGUCAUC 5576 AUGACAGCCCUCUCUGACU 5577 AGUCAGAGAGGGCUGUCAU 5578 UGACAGCCCUCUCUGACUU 5579 AAGUCAGAGAGGGCUGUCA 5580 GACAGCCCUCUCUGACUUU 5581 AAAGUCAGAGAGGGCUGUC 5582 ACAGCCCUCUCUGACUUUA 5583 UAAAGUCAGAGAGGGCUGU 5584 CAGCCCUCUCUGACUUUAC 5585 GUAAAGUCAGAGAGGGCUG 5586 AGCCCUCUCUGACUUUACC 5587 GGUAAAGUCAGAGAGGGCU 5588 GCCCUCUCUGACUUUACCU 5589 AGGUAAAGUCAGAGAGGGC 5590 CCCUCUCUGACUUUACCUU 5591 AAGGUAAAGUCAGAGAGGG 5592 CCUCUCUGACUUUACCUUG 5593 CAAGGUAAAGUCAGAGAGG 5594 CUCUCUGACUUUACCUUGA 5595 UCAAGGUAAAGUCAGAGAG 5596 AGAUCUGUCUUCAUACCCU 5597 AGGGUAUGAAGACAGAUCU 5598 GAUCUGUCUUCAUACCCUU 5599 AAGGGUAUGAAGACAGAUC 5600 CUGUCUUCAUACCCUUCCC 5601 GGGAAGGGUAUGAAGACAG 5602

In some embodiments, the siRNA molecules targeted to Transcript B comprise or consist of the nucleotide sequences (sense and antisense strands) shown in Table 9.

TABLE 9 SEQ SEQ ID ID Sense Sequence NO: Antisense Sequence NO: CCAGAGCAAGCCGAAGGCA 5603 UGCCUUCGGCUUGCUCUGG 5604 CAGAGCAAGCCGAAGGCAA 5605 UUGCCUUCGGCUUGCUCUG 5606 AGAGCAAGCCGAAGGCAAG 5607 CUUGCCUUCGGCUUGCUCU 5608 GAGCAAGCCGAAGGCAAGC 5609 GCUUGCCUUCGGCUUGCUC 5610 AGCAAGCCGAAGGCAAGCA 5611 UGCUUGCCUUCGGCUUGCU 5612 GCAAGCCGAAGGCAAGCAC 5613 GUGCUUGCCUUCGGCUUGC 5614 CAAGCCGAAGGCAAGCACG 5615 CGUGCUUGCCUUCGGCUUG 5616 AAGCCGAAGGCAAGCACGA 5617 UCGUGCUUGCCUUCGGCUU 5618 AGCCGAAGGCAAGCACGAU 5619 AUCGUGCUUGCCUUCGGCU 5620 GCCGAAGGCAAGCACGAUG 5621 CAUCGUGCUUGCCUUCGGC 5622 AAGGCAAGCACGAUGGCGC 5623 GCGCCAUCGUGCUUGCCUU 5624 AGGCAAGCACGAUGGCGCU 5625 AGCGCCAUCGUGCUUGCCU 5626 AAGCACGAUGGCGCUCACC 5627 GGUGAGCGCCAUCGUGCUU 5628 AGCACGAUGGCGCUCACCA 5629 UGGUGAGCGCCAUCGUGCU 5630 CUGUAGCAGCCGAGCAUCA 5631 UGAUGCUCGGCUGCUACAG 5632 AGCCGAGCAUCAGCCCGAA 5633 UUCGGGCUGAUGCUCGGCU 5634 GUCAGAGUCUCCAGGCUCA 5635 UGAGCCUGGAGACUCUGAC 5636 UCAGAGUCUCCAGGCUCAG 5637 CUGAGCCUGGAGACUCUGA 5638 CAGAGUCUCCAGGCUCAGG 5639 CCUGAGCCUGGAGACUCUG 5640 AGAGUCUCCAGGCUCAGGU 5641 ACCUGAGCCUGGAGACUCU 5642 GAGUCUCCAGGCUCAGGUG 5643 CACCUGAGCCUGGAGACUC 5644 AGUCUCCAGGCUCAGGUGG 5645 CCACCUGAGCCUGGAGACU 5646 GGGUGGCACAGCUGGCAUA 5647 UAUGCCAGCUGUGCCACCC 5648 GUGGCACAGCUGGCAUACG 5649 CGUAUGCCAGCUGUGCCAC 5650 UGGCACAGCUGGCAUACGC 5651 GCGUAUGCCAGCUGUGCCA 5652 CUCCACAGGUGGCGGUAGA 5653 UCUACCGCCACCUGUGGAG 5654 UCCACAGGUGGCGGUAGAC 5655 GUCUACCGCCACCUGUGGA 5656 UGAGCAGCACGCUGGCGUA 5657 UACGCCAGCGUGCUGCUCA 5658 AGCAGCACGCUGGCGUACA 5659 UGUACGCCAGCGUGCUGCU 5660 GCAGCACGCUGGCGUACAU 5661 AUGUACGCCAGCGUGCUGC 5662 CAGCACGCUGGCGUACAUG 5663 CAUGUACGCCAGCGUGCUG 5664 AGCACGCUGGCGUACAUGC 5665 GCAUGUACGCCAGCGUGCU 5666 GCACGCUGGCGUACAUGCU 5667 AGCAUGUACGCCAGCGUGC 5668 CACGCUGGCGUACAUGCUG 5669 CAGCAUGUACGCCAGCGUG 5670 ACGCUGGCGUACAUGCUGA 5671 UCAGCAUGUACGCCAGCGU 5672 CUGGCGUACAUGCUGAGCG 5673 CGCUCAGCAUGUACGCCAG 5674 UGGCGUACAUGCUGAGCGC 5675 GCGCUCAGCAUGUACGCCA 5676 CGCGCACACGUAGUACACC 5677 GGUGUACUACGUGUGCGCG 5678 GCGCACACGUAGUACACCG 5679 CGGUGUACUACGUGUGCGC 5680 CGCACACGUAGUACACCGC 5681 GCGGUGUACUACGUGUGCG 5682 GCACACGUAGUACACCGCC 5683 GGCGGUGUACUACGUGUGC 5684 CACACGUAGUACACCGCCU 5685 AGGCGGUGUACUACGUGUG 5686 ACACGUAGUACACCGCCUU 5687 AAGGCGGUGUACUACGUGU 5688 CACGUAGUACACCGCCUUG 5689 CAAGGCGGUGUACUACGUG 5690 UAGUACACCGCCUUGCAGC 5691 GCUGCAAGGCGGUGUACUA 5692 CCAAGCUCCACACCACGAA 5693 UUCGUGGUGUGGAGCUUGG 5694 CAAGCUCCACACCACGAAG 5695 CUUCGUGGUGUGGAGCUUG 5696 AAGCUCCACACCACGAAGC 5697 GCUUCGUGGUGUGGAGCUU 5698 AGCUCCACACCACGAAGCC 5699 GGCUUCGUGGUGUGGAGCU 5700 CUCCACACCACGAAGCCGU 5701 ACGGCUUCGUGGUGUGGAG 5702 UCCACACCACGAAGCCGUU 5703 AACGGCUUCGUGGUGUGGA 5704 CCACACCACGAAGCCGUUG 5705 CAACGGCUUCGUGGUGUGG 5706 CACACCACGAAGCCGUUGC 5707 GCAACGGCUUCGUGGUGUG 5708 ACACCACGAAGCCGUUGCC 5709 GGCAACGGCUUCGUGGUGU 5710 CACCACGAAGCCGUUGCCA 5711 UGGCAACGGCUUCGUGGUG 5712 ACCACGAAGCCGUUGCCAG 5713 CUGGCAACGGCUUCGUGGU 5714 CCGCGAAGUCUUCCAGCUC 5715 GAGCUGGAAGACUUCGCGG 5716 CGCGAAGUCUUCCAGCUCA 5717 UGAGCUGGAAGACUUCGCG 5718 GCGAAGUCUUCCAGCUCAG 5719 CUGAGCUGGAAGACUUCGC 5720 UUCCAGCUCAGCAGUGUCU 5721 AGACACUGCUGAGCUGGAA 5722 UCCAGCUCAGCAGUGUCUC 5723 GAGACACUGCUGAGCUGGA 5724 CCAGCUCAGCAGUGUCUCG 5725 CGAGACACUGCUGAGCUGG 5726 CAGCUCAGCAGUGUCUCGU 5727 ACGAGACACUGCUGAGCUG 5728 AGCUCAGCAGUGUCUCGUU 5729 AACGAGACACUGCUGAGCU 5730 GCUCAGCAGUGUCUCGUUC 5731 GAACGAGACACUGCUGAGC 5732 CUCAGCAGUGUCUCGUUCC 5733 GGAACGAGACACUGCUGAG 5734 GUAGCAGACCGACAUCCUU 5735 AAGGAUGUCGGUCUGCUAC 5736 UAGCAGACCGACAUCCUUC 5737 GAAGGAUGUCGGUCUGCUA 5738 AGCAGACCGACAUCCUUCU 5739 AGAAGGAUGUCGGUCUGCU 5740 AGACCGACAUCCUUCUGGG 5741 CCCAGAAGGAUGUCGGUCU 5742 GACCGACAUCCUUCUGGGC 5743 GCCCAGAAGGAUGUCGGUC 5744 CCGACAUCCUUCUGGGCCU 5745 AGGCCCAGAAGGAUGUCGG 5746 CGACAUCCUUCUGGGCCUA 5747 UAGGCCCAGAAGGAUGUCG 5748 GACAUCCUUCUGGGCCUAC 5749 GUAGGCCCAGAAGGAUGUC 5750 CUUCUGGGCCUACAGGUGG 5751 CCACCUGUAGGCCCAGAAG 5752 UUCUGGGCCUACAGGUGGG 5753 CCCACCUGUAGGCCCAGAA 5754 UCUGGGCCUACAGGUGGGU 5755 ACCCACCUGUAGGCCCAGA 5756 GGCCUACAGGUGGGUGGAA 5757 UUCCACCCACCUGUAGGCC 5758 CCUACAGGUGGGUGGAAGG 5759 CCUUCCACCCACCUGUAGG 5760 CUACAGGUGGGUGGAAGGC 5761 GCCUUCCACCCACCUGUAG 5762 UACAGGUGGGUGGAAGGCG 5763 CGCCUUCCACCCACCUGUA 5764 ACUUCCCUGCAGCCUGCCU 5765 AGGCAGGCUGCAGGGAAGU 5766 CCUGCAGCCUGCCUCUUUU 5767 AAAAGAGGCAGGCUGCAGG 5768 CUGCAGCCUGCCUCUUUUC 5769 GAAAAGAGGCAGGCUGCAG 5770 GCAGCCUGCCUCUUUUCUG 5771 CAGAAAAGAGGCAGGCUGC 5772 CAGCCUGCCUCUUUUCUGC 5773 GCAGAAAAGAGGCAGGCUG 5774 AGCCUGCCUCUUUUCUGCC 5775 GGCAGAAAAGAGGCAGGCU 5776 GCCUCUUUUCUGCCUGGGA 5777 UCCCAGGCAGAAAAGAGGC 5778 CUUUUCUGCCUGGGAGUCC 5779 GGACUCCCAGGCAGAAAAG 5780 UUUUCUGCCUGGGAGUCCU 5781 AGGACUCCCAGGCAGAAAA 5782 UUCUGCCUGGGAGUCCUGA 5783 UCAGGACUCCCAGGCAGAA 5784 UCUGCCUGGGAGUCCUGAC 5785 GUCAGGACUCCCAGGCAGA 5786 UGCCUGGGAGUCCUGACUU 5787 AAGUCAGGACUCCCAGGCA 5788 GCCUGGGAGUCCUGACUUC 5789 GAAGUCAGGACUCCCAGGC 5790 CUGGGAGUCCUGACUUCCA 5791 UGGAAGUCAGGACUCCCAG 5792 UGGGAGUCCUGACUUCCAC 5793 GUGGAAGUCAGGACUCCCA 5794 GGGAGUCCUGACUUCCACG 5795 CGUGGAAGUCAGGACUCCC 5796 GGAGUCCUGACUUCCACGA 5797 UCGUGGAAGUCAGGACUCC 5798 GAGUCCUGACUUCCACGAG 5799 CUCGUGGAAGUCAGGACUC 5800 AGUCCUGACUUCCACGAGG 5801 CCUCGUGGAAGUCAGGACU 5802 CCUGACUUCCACGAGGACC 5803 GGUCCUCGUGGAAGUCAGG 5804 CUGACUUCCACGAGGACCC 5805 GGGUCCUCGUGGAAGUCAG 5806 UGACUUCCACGAGGACCCA 5807 UGGGUCCUCGUGGAAGUCA 5808 GACUUCCACGAGGACCCAG 5809 CUGGGUCCUCGUGGAAGUC 5810 ACUUCCACGAGGACCCAGA 5811 UCUGGGUCCUCGUGGAAGU 5812 CuUCCACGAGGACCCAGAC 5813 GUCUGGGUCCUCGUGGAAG 5814 UUCCACGAGGACCCAGACC 5815 GGUCUGGGUCCUCGUGGAA 5816 CCCUGCUCCCAGUCAGUUG 5817 CAACUGACUGGGAGCAGGG 5818 CCUGCUCCCAGUCAGUUGA 5819 UCAACUGACUGGGAGCAGG 5820 CUGCUCCCAGUCAGUUGAC 5821 GUCAACUGACUGGGAGCAG 5822 UGCUCCCAGUCAGUUGACC 5823 GGUCAACUGACUGGGAGCA 5824 CCCAGUCAGUUGACCUGCC 5825 GGCAGGUCAACUGACUGGG 5826 CCAGUCAGUUGACCUGCCC 5827 GGGCAGGUCAACUGACUGG 5828 GCCUCCUUCCCAGAGCUCA 5829 UGAGCUCUGGGAAGGAGGC 5830 CCUCCUUCCCAGAGCUCAG 5831 CUGAGCUCUGGGAAGGAGG 5832 CUCCUUCCCAGAGCUCAGU 5833 ACUGAGCUCUGGGAAGGAG 5834 UCCUUCCCAGAGCUCAGUG 5835 CACUGAGCUCUGGGAAGGA 5836 CCUUCCCAGAGCUCAGUGG 5837 CCACUGAGCUCUGGGAAGG 5838 UUCCCAGAGCUCAGUGGUA 5839 UACCACUGAGCUCUGGGAA 5840 UCCCAGAGCUCAGUGGUAA 5841 UUACCACUGAGCUCUGGGA 5842 CAGGCUGUCACUAUCUCUA 5843 UAGAGAUAGUGACAGCCUG 5844 AGGCUGUCACUAUCUCUAC 5845 GUAGAGAUAGUGACAGCCU 5846 UCUCUACCACCACUCCUCU 5847 AGAGGAGUGGUGGUAGAGA 5848 CCACCACUCCUCUAGUCUG 5849 CAGACUAGAGGAGUGGUGG 5850 CACCACUCCUCUAGUCUGG 5851 CCAGACUAGAGGAGUGGUG 5852 ACCACUCCUCUAGUCUGGC 5853 GCCAGACUAGAGGAGUGGU 5854 CCACUCCUCUAGUCUGGCC 5855 GGCCAGACUAGAGGAGUGG 5856 CACUCCUCUAGUCUGGCCC 5857 GGGCCAGACUAGAGGAGUG 5858 AUUCUAGCACAUCUGGGCA 5859 UGCCCAGAUGUGCUAGAAU 5860 UUCUAGCACAUCUGGGCAA 5861 UUGCCCAGAUGUGCUAGAA 5862 UCUAGCACAUCUGGGCAAA 5863 UUUGCCCAGAUGUGCUAGA 5864 CUAGCACAUCUGGGCAAAA 5865 UUUUGCCCAGAUGUGCUAG 5866 GGGUGUAAAGGGACGUGCA 5867 UGCACGUCCCUUUACACCC 5868 GGUGUAAAGGGACGUGCAC 5869 GUGCACGUCCCUUUACACC 5870 GUGUAAAGGGACGUGCACA 5871 UGUGCACGUCCCUUUACAC 5872 UGUAAAGGGACGUGCACAG 5873 CUGUGCACGUCCCUUUACA 5874 GUAAAGGGACGUGCACAGA 5875 UCUGUGCACGUCCCUUUAC 5876 UAAAGGGACGUGCACAGAU 5877 AUCUGUGCACGUCCCUUUA 5878 AAAGGGACGUGCACAGAUC 5879 GAUCUGUGCACGUCCCUUU 5880 AAGGGACGUGCACAGAUCU 5881 AGAUCUGUGCACGUCCCUU 5882 AGGGACGUGCACAGAUCUA 5883 UAGAUCUGUGCACGUCCCU 5884 CGUGCACAGAUCUACUUAC 5885 GUAAGUAGAUCUGUGCACG 5886 GUGCACAGAUCUACUUACC 5887 GGUAAGUAGAUCUGUGCAC 5888 UGCACAGAUCUACUUACCA 5889 UGGUAAGUAGAUCUGUGCA 5890 GCACAGAUCUACUUACCAA 5891 UUGGUAAGUAGAUCUGUGC 5892 CACAGAUCUACUUACCAAG 5893 CUUGGUAAGUAGAUCUGUG 5894 ACAGAUCUACUUACCAAGC 5895 GCUUGGUAAGUAGAUCUGU 5896 CAGAUCUACUUACCAAGCU 5897 AGCUUGGUAAGUAGAUCUG 5898 AGAUCUACUUACCAAGCUG 5899 CAGCUUGGUAAGUAGAUCU 5900 AUCUACUUACCAAGCUGGG 5901 CCCAGCUUGGUAAGUAGAU 5902 UCUACUUACCAAGCUGGGA 5903 UCCCAGCUUGGUAAGUAGA 5904 CUUACCAAGCUGGGAGCAA 5905 UUGCUCCCAGCUUGGUAAG 5906 UUACCAAGCUGGGAGCAAG 5907 CUUGCUCCCAGCUUGGUAA 5908 UACCAAGCUGGGAGCAAGC 5909 GCUUGCUCCCAGCUUGGUA 5910 ACCAAGCUGGGAGCAAGCA 5911 UGCUUGCUCCCAGCUUGGU 5912 GCUGGGAGCAAGCAGGAUU 5913 AAUCCUGCUUGCUCCCAGC 5914 CUGGGAGCAAGCAGGAUUG 5915 CAAUCCUGCUUGCUCCCAG 5916 UGGGAGCAAGCAGGAUUGG 5917 CCAAUCCUGCUUGCUCCCA 5918 GGGAGCAAGCAGGAUUGGG 5919 CCCAAUCCUGCUUGCUCCC 5920 AAAGGUUAAGCAGCAGUAG 5921 CUACUGCUGCUUAACCUUU 5922 AAGGUUAAGCAGCAGUAGG 5923 CCUACUGCUGCUUAACCUU 5924 AGGUUAAGCAGCAGUAGGC 5925 GCCUACUGCUGCUUAACCU 5926 GGUGCCUACUCCUGUCCUG 5927 CAGGACAGGAGUAGGCACC 5928 GUGCCUACUCCUGUCCUGU 5929 ACAGGACAGGAGUAGGCAC 5930 UGCCUACUCCUGUCCUGUG 5931 CACAGGACAGGAGUAGGCA 5932 GCCUACUCCUGUCCUGUGC 5933 GCACAGGACAGGAGUAGGC 5934 CCUACUCCUGUCCUGUGCC 5935 GGCACAGGACAGGAGUAGG 5936 CUACUCCUGUCCUGUGCCU 5937 AGGCACAGGACAGGAGUAG 5938 UACUCCUGUCCUGUGCCUA 5939 UAGGCACAGGACAGGAGUA 5940 ACUCCUGUCCUGUGCCUAU 5941 AUAGGCACAGGACAGGAGU 5942 CUCCUGUCCUGUGCCUAUC 5943 GAUAGGCACAGGACAGGAG 5944 UCCUGUCCUGUGCCUAUCA 5945 UGAUAGGCACAGGACAGGA 5946 GUGCCUAUCACAUUUGCAG 5947 CUGCAAAUGUGAUAGGCAC 5948 CUAUCACAUUUGCAGAGGG 5949 CCCUCUGCAAAUGUGAUAG 5950 UAUCACAUUUGCAGAGGGU 5951 ACCCUCUGCAAAUGUGAUA 5952 AUCACAUUUGCAGAGGGUA 5953 UACCCUCUGCAAAUGUGAU 5954 UCACAUUUGCAGAGGGUAA 5955 UUACCCUCUGCAAAUGUGA 5956 CACAUUUGCAGAGGGUAAG 5957 CUUACCCUCUGCAAAUGUG 5958 ACAUUUGCAGAGGGUAAGA 5959 UCUUACCCUCUGCAAAUGU 5960 CUCACCCUGCUCCUUCCCA 5961 UGGGAAGGAGCAGGGUGAG 5962 CACCCUGCUCCUUCCCAUC 5963 GAUGGGAAGGAGCAGGGUG 5964 CCUGCUCCUUCCCAUCACC 5965 GGUGAUGGGAAGGAGCAGG 5966 UGCUCCUUCCCAUCACCAA 5967 UUGGUGAUGGGAAGGAGCA 5968 CAGUAAGAUUCCCUGGUGG 5969 CCACCAGGGAAUCUUACUG 5970 AGUAAGAUUCCCUGGUGGU 5971 ACCACCAGGGAAUCUUACU 5972 GUAAGAUUCCCUGGUGGUG 5973 CACCACCAGGGAAUCUUAC 5974 UAAGAUUCCCUGGUGGUGG 5975 CCACCACCAGGGAAUCUUA 5976 AAGAUUCCCUGGUGGUGGA 5977 UCCACCACCAGGGAAUCUU 5978 UCCCUGGUGGUGGAAGGAA 5979 UUCCUUCCACCACCAGGGA 5980 UCUGCUGAAUCCUGGUCCU 5981 AGGACCAGGAUUCAGCAGA 5982 CUGCUGAAUCCUGGUCCUG 5983 CAGGACCAGGAUUCAGCAG 5984 UGCUGAAUCCUGGUCCUGC 5985 GCAGGACCAGGAUUCAGCA 5986 UGAAUCCUGGUCCUGCUUC 5987 GAAGCAGGACCAGGAUUCA 5988 GAAUCCUGGUCCUGCUUCU 5989 AGAAGCAGGACCAGGAUUC 5990 AAUCCUGGUCCUGCUUCUG 5991 CAGAAGCAGGACCAGGAUU 5992 AUCCUGGUCCUGCUUCUGU 5993 ACAGAAGCAGGACCAGGAU 5994 UCCUGGUCCUGCUUCUGUU 5995 AACAGAAGCAGGACCAGGA 5996 CCUGGUCCUGCUUCUGUUC 5997 GAACAGAAGCAGGACCAGG 5998 CUGGUCCUGCUUCUGUUCU 5999 AGAACAGAAGCAGGACCAG 6000 UUCUGUUCUCAUCCCUCCC 6001 GGGAGGGAUGAGAACAGAA 6002 CUUCUGCAGUGUGUAUGUU 6003 AACAUACACACUGCAGAAG 6004 UUCUGCAGUGUGUAUGUUG 6005 CAACAUACACACUGCAGAA 6006 UCUGCAGUGUGUAUGUUGC 6007 GCAACAUACACACUGCAGA 6008 CUGCAGUGUGUAUGUUGCC 6009 GGCAACAUACACACUGCAG 6010 UGCAGUGUGUAUGUUGCCU 6011 AGGCAACAUACACACUGCA 6012 GCAGUGUGUAUGUUGCCUG 6013 CAGGCAACAUACACACUGC 6014 CAGUGUGUAUGUUGCCUGG 6015 CCAGGCAACAUACACACUG 6016 AGUGUGUAUGUUGCCUGGU 6017 ACCAGGCAACAUACACACU 6018 GUGUGUAUGUUGCCUGGUC 6019 GACCAGGCAACAUACACAC 6020 UGUGUAUGUUGCCUGGUCU 6021 AGACCAGGCAACAUACACA 6022 GUGUAUGUUGCCUGGUCUC 6023 GAGACCAGGCAACAUACAC 6024 UGUAUGUUGCCUGGUCUCU 6025 AGAGACCAGGCAACAUACA 6026 GUAUGUUGCCUGGUCUCUC 6027 GAGAGACCAGGCAACAUAC 6028 UAUGUUGCCUGGUCUCUCU 6029 AGAGAGACCAGGCAACAUA 6030 AUGUUGCCUGGUCUCUCUG 6031 CAGAGAGACCAGGCAACAU 6032 UGUUGCCUGGUCUCUCUGG 6033 CCAGAGAGACCAGGCAACA 6034 GUUGCCUGGUCUCUCUGGC 6035 GCCAGAGAGACCAGGCAAC 6036 UUGCCUGGUCUCUCUGGCC 6037 GGCCAGAGAGACCAGGCAA 6038 CUGGUCUCUCUGGCCUGCA 6039 UGCAGGCCAGAGAGACCAG 6040 CCUGCAGAGGUGACCCAAA 6041 UUUGGGUCACCUCUGCAGG 6042 CUGCCUUAUCCUUGCCUGU 6043 ACAGGCAAGGAUAAGGCAG 6044 UGCCUUAUCCUUGCCUGUU 6045 AACAGGCAAGGAUAAGGCA 6046 GCCUUAUCCUUGCCUGUUU 6047 AAACAGGCAAGGAUAAGGC 6048 AGUCUCCUGGUCCGGCUGA 6049 UCAGCCGGACCAGGAGACU 6050 GUCAAUGACAGCUUUUCCA 6051 UGGAAAAGCUGUCAUUGAC 6052 UGACAGCUUUUCCAUGUAA 6053 UUACAUGGAAAAGCUGUCA 6054 GACAGCUUUUCCAUGUAAG 6055 CUUACAUGGAAAAGCUGUC 6056 ACAGCUUUUCCAUGUAAGG 6057 CCUUACAUGGAAAAGCUGU 6058 CAGCUUUUCCAUGUAAGGC 6059 GCCUUACAUGGAAAAGCUG 6060 AGCUUUUCCAUGUAAGGCA 6061 UGCCUUACAUGGAAAAGCU 6062 UGUAAGGCAUGGUGCUAGG 6063 CCUAGCACCAUGCCUUACA 6064 GUAAGGCAUGGUGCUAGGU 6066 ACCUAGCACCAUGCCUUAC 6066 UAAGGCAUGGUGCUAGGUU 6067 AACCUAGCACCAUGCCUUA 6068 GCAUGGUGCUAGGUUCCAG 6069 CUGGAACCUAGCACCAUGC 6070 CAUGGUGCUAGGUUCCAGG 6071 CCUGGAACCUAGCACCAUG 6072 AUGGUGCUAGGUUCCAGGA 6073 UCCUGGAACCUAGCACCAU 6074 UGGUGCUAGGUUCCAGGAG 6076 CUCCUGGAACCUAGCACCA 6076 GGUGCUAGGUUCCAGGAGG 6077 CCUCCUGGAACCUAGCACC 6078 GUGCUAGGUUCCAGGAGGA 6079 UCCUCCUGGAACCUAGCAC 6080 UGCAUGGAGGCAUAAUGGU 6081 ACCAUUAUGCCUCCAUGCA 6082 GCAUGGAGGCAUAAUGGUU 6083 AACCAUUAUGCCUCCAUGC 6084 CAUGGAGGCAUAAUGGUUA 6086 UAACCAUUAUGCCUCCAUG 6086 AUGGAGGCAUAAUGGUUAG 6087 CUAACCAUUAUGCCUCCAU 6088 UGGAGGCAUAAUGGUUAGG 6089 CCUAACCAUUAUGCCUCCA 6090 GGAGGCAUAAUGGUUAGGG 6091 CCCUAACCAUUAUGCCUCC 6092 GAGGCAUAAUGGUUAGGGA 6093 UCCCUAACCAUUAUGCCUC 6094 CAUAAUGGUUAGGGAGUCA 6096 UGACUCCCUAACCAUUAUG 6096 AUAAUGGUUAGGGAGUCAU 6097 AUGACUCCCUAACCAUUAU 6098 UAAUGGUUAGGGAGUCAUG 6099 CAUGACUCCCUAACCAUUA 6100 GGUUAGGGAGUCAUGACAC 6101 GUGUCAUGACUCCCUAACC 6102 CAUUACCAGGCUGCACCAG 6103 CUGGUGCAGCCUGGUAAUG 6104 AUUACCAGGCUGCACCAGG 6105 CCUGGUGCAGCCUGGUAAU 6106 UACCAGGCUGCACCAGGAU 6107 AUCCUGGUGCAGCCUGGUA 6108 ACCAGGCUGCACCAGGAUA 6109 UAUCCUGGUGCAGCCUGGU 6110 CCAGGCUGCACCAGGAUAC 6111 GUAUCCUGGUGCAGCCUGG 6112 AAAGGAUGAGUAGGGACAU 6113 AUGUCCCUACUCAUCCUUU 6114 AAGGAUGAGUAGGGACAUA 6116 UAUGUCCCUACUCAUCCUU 6116 AGGAUGAGUAGGGACAUAC 6117 GUAUGUCCCUACUCAUCCU 6118 GUAGGGACAUACUAAGAAG 6119 CUUCUUAGUAUGUCCCUAC 6120 GGACAUACUAAGAAGCAGC 6121 GCUGCUUCUUAGUAUGUCC 6122 AUACUAAGAAGCAGCCCUC 6123 GAGGGCUGCUUCUUAGUAU 6124 UACUAAGAAGCAGCCCUCU 6125 AGAGGGCUGCUUCUUAGUA 6126 ACUAAGAAGCAGCCCUCUC 6127 GAGAGGGCUGCUUCUUAGU 6128 AGAAGCAGCCCUCUCCUCU 6129 AGAGGAGAGGGCUGCUUCU 6130 GAAGCAGCCCUCUCCUCUU 6131 AAGAGGAGAGGGCUGCUUC 6132 CAGCCCUCUCCUCUUGGAA 6133 UUCCAAGAGGAGAGGGCUG 6134 GCCUGGCAGAUGGAUAGAG 6136 CUCUAUCCAUCUGCCAGGC 6136 CCUGGCAGAUGGAUAGAGC 6137 GCUCUAUCCAUCUGCCAGG 6138 CUGGCAGAUGGAUAGAGCU 6139 AGCUCUAUCCAUCUGCCAG 6140 UGGCAGAUGGAUAGAGCUG 6141 CAGCUCUAUCCAUCUGCCA 6142 GGCAGAUGGAUAGAGCUGG 6143 CCAGCUCUAUCCAUCUGCC 6144 GCAGAUGGAUAGAGCUGGG 6145 CCCAGCUCUAUCCAUCUGC 6146 AAAGGCCUCUGCUCAAGUA 6147 UACUUGAGCAGAGGCCUUU 6148 AAGGCCUCUGCUCAAGUAA 6149 UUACUUGAGCAGAGGCCUU 6150 AGGCCUCUGCUCAAGUAAC 6151 GUUACUUGAGCAGAGGCCU 6152 CAGGAGCACUGUCUUAGUU 6153 AACUAAGACAGUGCUCCUG 6154 AGGAGCACUGUCUUAGUUU 6155 AAACUAAGACAGUGCUCCU 6156 GGAGCACUGUCUUAGUUUG 6157 CAAACUAAGACAGUGCUCC 6158 GAGCACUGUCUUAGUUUGG 6159 CCAAACUAAGACAGUGCUC 6160 AGCACUGUCUUAGUUUGGG 6161 CCCAAACUAAGACAGUGCU 6162 GUUCUUCCAAAGCAGAGCU 6163 AGCUCUGCUUUGGAAGAAC 6164 AGCAGAGCUUGAGCUAAGG 6165 CCUUAGCUCAAGCUCUGCU 6166 GCAGAGCUUGAGCUAAGGG 6167 CCCUUAGCUCAAGCUCUGC 6168 CAGAGCUUGAGCUAAGGGC 6169 GCCCUUAGCUCAAGCUCUG 6170 GCUUGAGCUAAGGGCUUGG 6171 CCAAGCCCUUAGCUCAAGC 6172 UUGAGCUAAGGGCUUGGGU 6173 ACCCAAGCCCUUAGCUCAA 6174 UGAGCUAAGGGCUUGGGUA 6175 UACCCAAGCCCUUAGCUCA 6176 GAGCUAAGGGCUUGGGUAC 6177 GUACCCAAGCCCUUAGCUC 6178 AGCUAAGGGCUUGGGUACA 6179 UGUACCCAAGCCCUUAGCU 6180 GCUAAGGGCUUGGGUACAG 6181 CUGUACCCAAGCCCUUAGC 6182 AGGGCUUGGGUACAGGUGA 6183 UCACCUGUACCCAAGCCCU 6184 GGGCUUGGGUACAGGUGAU 6185 AUCACCUGUACCCAAGCCC 6186 GGCUUGGGUACAGGUGAUC 6187 GAUCACCUGUACCCAAGCC 6188 GCUUGGGUACAGGUGAUCC 6189 GGAUCACCUGUACCCAAGC 6190 AGGUGAUCCUGUAUUCUUG 6191 CAAGAAUACAGGAUCACCU 6192 GGUGAUCCUGUAUUCUUGA 6193 UCAAGAAUACAGGAUCACC 6194 GUGAUCCUGUAUUCUUGAG 6195 CUCAAGAAUACAGGAUCAC 6196 UGAUCCUGUAUUCUUGAGC 6197 GCUCAAGAAUACAGGAUCA 6198 UCCUGUAUUCUUGAGCUAA 6199 UUAGCUCAAGAAUACAGGA 6200 CCUGUAUUCUUGAGCUAAG 6201 CUUAGCUCAAGAAUACAGG 6202 UGUAUUCUUGAGCUAAGGG 6203 CCCUUAGCUCAAGAAUACA 6204 GUAUUCUUGAGCUAAGGGC 6205 GCCCUUAGCUCAAGAAUAC 6206 UCUUGAGCUAAGGGCUUGG 6207 CCAAGCCCUUAGCUCAAGA 6208 UUGAGCUAAGGGCUUGGGU 6209 ACCCAAGCCCUUAGCUCAA 6210 UGAGCUAAGGGCUUGGGUA 6211 UACCCAAGCCCUUAGCUCA 6212 GAGCUAAGGGCUUGGGUAC 6213 GUACCCAAGCCCUUAGCUC 6214 AGCUAAGGGCUUGGGUACA 6215 UGUACCCAAGCCCUUAGCU 6216 GCUAAGGGCUUGGGUACAG 6217 CUGUACCCAAGCCCUUAGC 6218 AGGGCUUGGGUACAGGUGA 6219 UCACCUGUACCCAAGCCCU 6220 GGGCUUGGGUACAGGUGAU 6221 AUCACCUGUACCCAAGCCC 6222 GGCUUGGGUACAGGUGAUC 6223 GAUCACCUGUACCCAAGCC 6224 GCUUGGGUACAGGUGAUCC 6225 GGAUCACCUGUACCCAAGC 6226 AGGUGAUCCUGUAUUUGGG 6227 CCCAAAUACAGGAUCACCU 6228 GGUGAUCCUGUAUUUGGGA 6229 UCCCAAAUACAGGAUCACC 6230 AUCCUGUAUUUGGGAGGUU 6231 AACCUCCCAAAUACAGGAU 6232 UCCUGUAUUUGGGAGGUUA 6233 UAACCUCCCAAAUACAGGA 6234 CCUGUAUUUGGGAGGUUAA 6235 UUAACCUCCCAAAUACAGG 6236 CUGUAUUUGGGAGGUUAAC 6237 GUUAACCUCCCAAAUACAG 6238 UGUAUUUGGGAGGUUAACU 6239 AGUUAACCUCCCAAAUACA 6240 GUAUUUGGGAGGUUAACUC 6241 GAGUUAACCUCCCAAAUAC 6242 UAUUUGGGAGGUUAACUCA 6243 UGAGUUAACCUCCCAAAUA 6244 GGAGGUUAACUCAGGAAGU 6245 ACUUCCUGAGUUAACCUCC 6246 GAGGUUAACUCAGGAAGUG 6247 CACUUCCUGAGUUAACCUC 6248 AGGUUAACUCAGGAAGUGA 6249 UCACUUCCUGAGUUAACCU 6250 UCAGGAAGUGAGGGCAUAA 6251 UUAUGCCCUCACUUCCUGA 6252 CAGGAAGUGAGGGCAUAAG 6253 CUUAUGCCCUCACUUCCUG 6254 AGGAAGUGAGGGCAUAAGG 6255 CCUUAUGCCCUCACUUCCU 6256 GGAAGUGAGGGCAUAAGGU 6257 ACCUUAUGCCCUCACUUCC 6258 GAAGUGAGGGCAUAAGGUA 6259 UACCUUAUGCCCUCACUUC 6260 AAGUGAGGGCAUAAGGUAA 6261 UUACCUUAUGCCCUCACUU 6262 AGUGAGGGCAUAAGGUAAA 6263 UUUACCUUAUGCCCUCACU 6264 AAAGCCAUUAAGAGUAUGU 6265 ACAUACUCUUAAUGGCUUU 6266 AAGCCAUUAAGAGUAUGUU 6267 AACAUACUCUUAAUGGCUU 6268 AGCCAUUAAGAGUAUGUUA 6269 UAACAUACUCUUAAUGGCU 6270 UAAGAGUAUGUUAAGUCCC 6271 GGGACUUAACAUACUCUUA 6272 AAGAGUAUGUUAAGUCCCU 6273 AGGGACUUAACAUACUCUU 6274 AGAGUAUGUUAAGUCCCUU 6275 AAGGGACUUAACAUACUCU 6276 GAGUAUGUUAAGUCCCUUC 6277 GAAGGGACUUAACAUACUC 6278 AGUAUGUUAAGUCCCUUCA 6279 UGAAGGGACUUAACAUACU 6280 GUAUGUUAAGUCCCUUCAG 6281 CUGAAGGGACUUAACAUAC 6282 UAUGUUAAGUCCCUUCAGU 6283 ACUGAAGGGACUUAACAUA 6284 AUGUUAAGUCCCUUCAGUA 6285 UACUGAAGGGACUUAACAU 6286 UGUUAAGUCCCUUCAGUAG 6287 CUACUGAAGGGACUUAACA 6288 GUUAAGUCCCUUCAGUAGG 6289 CCUACUGAAGGGACUUAAC 6290 UUAAGUCCCUUCAGUAGGC 6291 GCCUACUGAAGGGACUUAA 6292 UAAGUCCCUUCAGUAGGCC 6293 GGCCUACUGAAGGGACUUA 6294 AAGUCCCUUCAGUAGGCCU 6295 AGGCCUACUGAAGGGACUU 6296 AGUCCCUUCAGUAGGCCUU 6297 AAGGCCUACUGAAGGGACU 6298 GUCCCUUCAGUAGGCCUUG 6299 CAAGGCCUACUGAAGGGAC 6300 UCCCUUCAGUAGGCCUUGG 6301 CCAAGGCCUACUGAAGGGA 6302 CCCUUCAGUAGGCCUUGGG 6303 CCCAAGGCCUACUGAAGGG 6304 CCUUCAGUAGGCCUUGGGA 6305 UCCCAAGGCCUACUGAAGG 6306 CUUCAGUAGGCCUUGGGAA 6307 UUCCCAAGGCCUACUGAAG 6308 AAAAGUAUAGAUUGCCCAA 6309 UUGGGCAAUCUAUACUUUU 6310 AAAGUAUAGAUUGCCCAAG 6311 CUUGGGCAAUCUAUACUUU 6312 AAGUAUAGAUUGCCCAAGA 6313 UCUUGGGCAAUCUAUACUU 6314 AAAGACUGGCAGGGUGAUC 6315 GAUCACCCUGCCAGUCUUU 6316 AAGACUGGCAGGGUGAUCA 6317 UGAUCACCCUGCCAGUCUU 6318 CUGGCAGGGUGAUCAGUCC 6319 GGACUGAUCACCCUGCCAG 6320 GAAUGUACUUAAUGAGUGG 6321 CCACUCAUUAAGUACAUUC 6322 AAUGUACUUAAUGAGUGGG 6323 CCCACUCAUUAAGUACAUU 6324 UGUACUUAAUGAGUGGGCU 6325 AGCCCACUCAUUAAGUACA 6326 GUACUUAAUGAGUGGGCUA 6327 UAGCCCACUCAUUAAGUAC 6328 UACUUAAUGAGUGGGCUAC 6329 GUAGCCCACUCAUUAAGUA 6330 CUUAAUGAGUGGGCUACAG 6331 CUGUAGCCCACUCAUUAAG 6332 UAAUGAGUGGGCUACAGCG 6333 CGCUGUAGCCCACUCAUUA 6334 AAUGAGUGGGCUACAGCGU 6335 ACGCUGUAGCCCACUCAUU 6336 AUGAGUGGGCUACAGCGUA 6337 UACGCUGUAGCCCACUCAU 6338 UGAGUGGGCUACAGCGUAU 6339 AUACGCUGUAGCCCACUCA 6340 GAGUGGGCUACAGCGUAUC 6341 GAUACGCUGUAGCCCACUC 6342 AGUGGGCUACAGCGUAUCC 6343 GGAUACGCUGUAGCCCACU 6344 GUGGGCUACAGCGUAUCCU 6345 AGGAUACGCUGUAGCCCAC 6346 UGGGCUACAGCGUAUCCUC 6347 GAGGAUACGCUGUAGCCCA 6348 AGAGUUGUUCUACCUGGGU 6349 ACCCAGGUAGAACAACUCU 6350 GAGUUGUUCUACCUGGGUA 6351 UACCCAGGUAGAACAACUC 6352 AGUUGUUCUACCUGGGUAU 6353 AUACCCAGGUAGAACAACU 6354 GUUGUUCUACCUGGGUAUA 6355 UAUACCCAGGUAGAACAAC 6356 UUGUUCUACCUGGGUAUAU 6357 AUAUACCCAGGUAGAACAA 6358 UGUUCUACCUGGGUAUAUC 6359 GAUAUACCCAGGUAGAACA 6360 GUUCUACCUGGGUAUAUCC 6361 GGAUAUACCCAGGUAGAAC 6362 UACCUGGGUAUAUCCAAAA 6363 UUUUGGAUAUACCCAGGUA 6364 AGGGUAUGGAGUUUACGAG 6365 CUCGUAAACUCCAUACCCU 6366 GGGUAUGGAGUUUACGAGG 6367 CCUCGUAAACUCCAUACCC 6368 GGUAUGGAGUUUACGAGGG 6369 CCCUCGUAAACUCCAUACC 6370 GUAUGGAGUUUACGAGGGU 6371 ACCCUCGUAAACUCCAUAC 6372 UAUGGAGUUUACGAGGGUU 6373 AACCCUCGUAAACUCCAUA 6374 AUGGAGUUUACGAGGGUUC 6375 GAACCCUCGUAAACUCCAU 6376 UGGAGUUUACGAGGGUUCA 6377 UGAACCCUCGUAAACUCCA 6378 GGAGUUUACGAGGGUUCAA 6379 UUGAACCCUCGUAAACUCC 6380 GAGUUUACGAGGGUUCAAG 6381 CUUGAACCCUCGUAAACUC 6382 AGUUUACGAGGGUUCAAGG 6383 CCUUGAACCCUCGUAAACU 6384 GUUUACGAGGGUUCAAGGU 6385 ACCUUGAACCCUCGUAAAC 6386 UUUACGAGGGUUCAAGGUA 6387 UACCUUGAACCCUCGUAAA 6388 CGAGGGUUCAAGGUAUUUG 6389 CAAAUACCUUGAACCCUCG 6390 GAGGGUUCAAGGUAUUUGG 6391 CCAAAUACCUUGAACCCUC 6392 AGGGUUCAAGGUAUUUGGU 6393 ACCAAAUACCUUGAACCCU 6394 GGGUUCAAGGUAUUUGGUU 6395 AACCAAAUACCUUGAACCC 6396 GGUUCAAGGUAUUUGGUUC 6397 GAACCAAAUACCUUGAACC 6398 GUUCAAGGUAUUUGGUUCA 6399 UGAACCAAAUACCUUGAAC 6400 UUCAAGGUAUUUGGUUCAG 6401 CUGAACCAAAUACCUUGAA 6402 UCAAGGUAUUUGGUUCAGG 6403 CCUGAACCAAAUACCUUGA 6404 CAACUGGCCAGGUCACAGG 6405 CCUGUGACCUGGCCAGUUG 6406 GCCAGGUCACAGGGCAAUC 6407 GAUUGCCCUGUGACCUGGC 6408 CCAGGUCACAGGGCAAUCA 6409 UGAUUGCCCUGUGACCUGG 6410 AGGUCACAGGGCAAUCAAG 6411 CUUGAUUGCCCUGUGACCU 6412 GGUCACAGGGCAAUCAAGU 6413 ACUUGAUUGCCCUGUGACC 6414 GUCACAGGGCAAUCAAGUU 6415 AACUUGAUUGCCCUGUGAC 6416 UCACAGGGCAAUCAAGUUA 6417 UAACUUGAUUGCCCUGUGA 6418 CACAGGGCAAUCAAGUUAC 6419 GUAACUUGAUUGCCCUGUG 6420 ACAGGGCAAUCAAGUUACU 6421 AGUAACUUGAUUGCCCUGU 6422 CAGGGCAAUCAAGUUACUC 6423 GAGUAACUUGAUUGCCCUG 6424 AGGGCAAUCAAGUUACUCU 6425 AGAGUAACUUGAUUGCCCU 6426 CAAUCAAGUUACUCUGUGU 6427 ACACAGAGUAACUUGAUUG 6428 AAUCAAGUUACUCUGUGUU 6429 AACACAGAGUAACUUGAUU 6430 AUCAAGUUACUCUGUGUUU 6431 AAACACAGAGUAACUUGAU 6432 ACUCUGUGUUUCUUUGUCA 6433 UGACAAAGAAACACAGAGU 6434 UCUGUGUUUCUUUGUCAGG 6435 CCUGACAAAGAAACACAGA 6436 UGUUUCUUUGUCAGGACAC 6437 GUGUCCUGACAAAGAAACA 6438 AAAGCAGGGAUUGUGUUCA 6439 UGAACACAAUCCCUGCUUU 6440 AAGCAGGGAUUGUGUUCAU 6441 AUGAACACAAUCCCUGCUU 6442 AGCAGGGAUUGUGUUCAUU 6443 AAUGAACACAAUCCCUGCU 6444 GCAGGGAUUGUGUUCAUUU 6445 AAAUGAACACAAUCCCUGC 6446 CAGGGAUUGUGUUCAUUUG 6447 CAAAUGAACACAAUCCCUG 6448 AGGGAUUGUGUUCAUUUGA 6449 UCAAAUGAACACAAUCCCU 6450 GUGUUCAUUUGAGGGUUUC 6451 GAAACCCUCAAAUGAACAC 6452 UGUUCAUUUGAGGGUUUCA 6453 UGAAACCCUCAAAUGAACA 6454 GUUCAUUUGAGGGUUUCAC 6455 GUGAAACCCUCAAAUGAAC 6456 UUCAUUUGAGGGUUUCACU 6457 AGUGAAACCCUCAAAUGAA 6458 UCAUUUGAGGGUUUCACUG 6459 CAGUGAAACCCUCAAAUGA 6460 CAUUUGAGGGUUUCACUGU 6461 ACAGUGAAACCCUCAAAUG 6462 AGUCUCAGCUUCCAUGCAA 6463 UUGCAUGGAAGCUGAGACU 6464 UCUCAGCUUCCAUGCAACU 6465 AGUUGCAUGGAAGCUGAGA 6466 CUCAGCUUCCAUGCAACUG 6467 CAGUUGCAUGGAAGCUGAG 6468 UCAGCUUCCAUGCAACUGU 6469 ACAGUUGCAUGGAAGCUGA 6470 CAGCUUCCAUGCAACUGUC 6471 GACAGUUGCAUGGAAGCUG 6472 AGCUUCCAUGCAACUGUCC 6473 GGACAGUUGCAUGGAAGCU 6474 GCUUCCAUGCAACUGUCCA 6475 UGGACAGUUGCAUGGAAGC 6476 CUUCCAUGCAACUGUCCAU 6477 AUGGACAGUUGCAUGGAAG 6478 UUCCAUGCAACUGUCCAUC 6479 GAUGGACAGUUGCAUGGAA 6480 CCAUGCAACUGUCCAUCAC 6481 GUGAUGGACAGUUGCAUGG 6482 CAUGCAACUGUCCAUCACG 6483 CGUGAUGGACAGUUGCAUG 6484 AUGCAACUGUCCAUCACGG 6485 CCGUGAUGGACAGUUGCAU 6486 UGCAACUGUCCAUCACGGC 6487 GCCGUGAUGGACAGUUGCA 6488 GCAACUGUCCAUCACGGCU 6489 AGCCGUGAUGGACAGUUGC 6490 CAACUGUCCAUCACGGCUG 6491 CAGCCGUGAUGGACAGUUG 6492 AACUGUCCAUCACGGCUGC 6493 GCAGCCGUGAUGGACAGUU 6494 ACUGUCCAUCACGGCUGCA 6495 UGCAGCCGUGAUGGACAGU 6496 CUGUCCAUCACGGCUGCAA 6497 UUGCAGCCGUGAUGGACAG 6498 UGUCCAUCACGGCUGCAAC 6499 GUUGCAGCCGUGAUGGACA 6500 GUCCAUCACGGCUGCAACU 6501 AGUUGCAGCCGUGAUGGAC 6502 UCCAUCACGGCUGCAACUG 6503 CAGUUGCAGCCGUGAUGGA 6504 CCAUCACGGCUGCAACUGA 6505 UCAGUUGCAGCCGUGAUGG 6506 CAUCACGGCUGCAACUGAA 6507 UUCAGUUGCAGCCGUGAUG 6508 ACAGCGCACCAGAAGCUAA 6509 UUAGCUUCUGGUGCGCUGU 6510 CAGCGCACCAGAAGCUAAA 6511 UUUAGCUUCUGGUGCGCUG 6512 AGCGCACCAGAAGCUAAAG 6513 CUUUAGCUUCUGGUGCGCU 6514 GCGCACCAGAAGCUAAAGU 6515 ACUUUAGCUUCUGGUGCGC 6516 CGCACCAGAAGCUAAAGUC 6517 GACUUUAGCUUCUGGUGCG 6518 GCACCAGAAGCUAAAGUCU 6519 AGACUUUAGCUUCUGGUGC 6520 CACCAGAAGCUAAAGUCUU 6521 AAGACUUUAGCUUCUGGUG 6522 ACCAGAAGCUAAAGUCUUG 6523 CAAGACUUUAGCUUCUGGU 6524 CCAGAAGCUAAAGUCUUGA 6525 UCAAGACUUUAGCUUCUGG 6526 CAGAAGCUAAAGUCUUGAU 6527 AUCAAGACUUUAGCUUCUG 6528 AGAAGCUAAAGUCUUGAUG 6529 CAUCAAGACUUUAGCUUCU 6530 GAAGCUAAAGUCUUGAUGC 6531 GCAUCAAGACUUUAGCUUC 6532 AAGCUAAAGUCUUGAUGCC 6533 GGCAUCAAGACUUUAGCUU 6534 AGCUAAAGUCUUGAUGCCA 6535 UGGCAUCAAGACUUUAGCU 6536 CCCAUUCACAUCUCUGUCA 6537 UGACAGAGAUGUGAAUGGG 6538 UUCACAUCUCUGUCACGUC 6539 GACGUGACAGAGAUGUGAA 6540 UCACAUCUCUGUCACGUCC 6541 GGACGUGACAGAGAUGUGA 6542 CACAUCUCUGUCACGUCCA 6543 UGGACGUGACAGAGAUGUG 6544 UCUCUGUCACGUCCACUAA 6545 UUAGUGGACGUGACAGAGA 6546 CUCUGUCACGUCCACUAAU 6547 AUUAGUGGACGUGACAGAG 6548 UCUGUCACGUCCACUAAUC 6549 GAUUAGUGGACGUGACAGA 6550 CUGUCACGUCCACUAAUCG 6551 CGAUUAGUGGACGUGACAG 6552 UGUCACGUCCACUAAUCGG 6553 CCGAUUAGUGGACGUGACA 6554 GUCACGUCCACUAAUCGGC 6555 GCCGAUUAGUGGACGUGAC 6556 UCACGUCCACUAAUCGGCA 6557 UGCCGAUUAGUGGACGUGA 6558 CACGUCCACUAAUCGGCAA 6559 UUGCCGAUUAGUGGACGUG 6560 ACGUCCACUAAUCGGCAAA 6561 UUUGCCGAUUAGUGGACGU 6562 CGUCCACUAAUCGGCAAAA 6563 UUUUGCCGAUUAGUGGACG 6564 GUCCACUAAUCGGCAAAAG 6565 CUUUUGCCGAUUAGUGGAC 6566 UCCACUAAUCGGCAAAAGG 6567 CCUUUUGCCGAUUAGUGGA 6568 CCACUAAUCGGCAAAAGGA 6569 UCCUUUUGCCGAUUAGUGG 6570 CACUAAUCGGCAAAAGGAG 6571 CUCCUUUUGCCGAUUAGUG 6572 AGAAGAUGACCUAAGUGUG 6573 CACACUUAGGUCAUCUUCU 6574 GAAGAUGACCUAAGUGUGA 6575 UCACACUUAGGUCAUCUUC 6576 AAGAUGACCUAAGUGUGAC 6577 GUCACACUUAGGUCAUCUU 6578 AGAUGACCUAAGUGUGACU 6579 AGUCACACUUAGGUCAUCU 6580 GAUGACCUAAGUGUGACUG 6581 CAGUCACACUUAGGUCAUC 6582 AUGACCUAAGUGUGACUGC 6583 GCAGUCACACUUAGGUCAU 6584 UGACCUAAGUGUGACUGCA 6585 UGCAGUCACACUUAGGUCA 6586 AAAAUGAAGCCAGAGCAGU 6587 ACUGCUCUGGCUUCAUUUU 6588 UCCGACCAAGGAGGAAGGA 6589 UCCUUCCUCCUUGGUCGGA 6590 CCGACCAAGGAGGAAGGAA 6591 UUCCUUCCUCCUUGGUCGG 6592 AGAGCAGGUAAGCAGGAAG 6593 CUUCCUGCUUACCUGCUCU 6594 GAGCAGGUAAGCAGGAAGG 6595 CCUUCCUGCUUACCUGCUC 6596 AGGUAAGCAGGAAGGCCAG 6597 CUGGCCUUCCUGCUUACCU 6598 AGCAGGAAGGCCAGUGUCC 6599 GGACACUGGCCUUCCUGCU 6600 CAGGAAGGCCAGUGUCCCA 6601 UGGGACACUGGCCUUCCUG 6602 UCCCAGACAGGACCCUAAU 6603 AUUAGGGUCCUGUCUGGGA 6604 CCCAGACAGGACCCUAAUG 6605 CAUUAGGGUCCUGUCUGGG 6606 CCAGACAGGACCCUAAUGA 6607 UCAUUAGGGUCCUGUCUGG 6608 CAGACAGGACCCUAAUGAU 6609 AUCAUUAGGGUCCUGUCUG 6610 AGACAGGACCCUAAUGAUC 6611 GAUCAUUAGGGUCCUGUCU 6612 GACAGGACCCUAAUGAUCC 6613 GGAUCAUUAGGGUCCUGUC 6614 GGACCCUAAUGAUCCUGAA 6615 UUCAGGAUCAUUAGGGUCC 6616 CCUAAUGAUCCUGAAUCCA 6617 UGGAUUCAGGAUCAUUAGG 6618 CUAAUGAUCCUGAAUCCAU 6619 AUGGAUUCAGGAUCAUUAG 6620 UGAUCCUGAAUCCAUGUAU 6621 AUACAUGGAUUCAGGAUCA 6622 GAUCCUGAAUCCAUGUAUC 6623 GAUACAUGGAUUCAGGAUC 6624 AUCCUGAAUCCAUGUAUCA 6625 UGAUACAUGGAUUCAGGAU 6626 UCCAUGUAUCAGGAUCCAU 6627 AUGGAUCCUGAUACAUGGA 6628 CCAUGUAUCAGGAUCCAUC 6629 GAUGGAUCCUGAUACAUGG 6630 CAUGUAUCAGGAUCCAUCC 6631 GGAUGGAUCCUGAUACAUG 6632 UCACCUCUCAUUUUCCAAA 6633 UUUGGAAAAUGAGAGGUGA 6634 UCCAAAGCCCUGCCAUGCU 6635 AGCAUGGCAGGGCUUUGGA 6636 CCAAAGCCCUGCCAUGCUG 6637 CAGCAUGGCAGGGCUUUGG 6638 CAUGCUGCCAUCCCACUUC 6639 GAAGUGGGAUGGCAGCAUG 6640 AUGCUGCCAUCCCACUUCC 6641 GGAAGUGGGAUGGCAGCAU 6642 UGCUGCCAUCCCACUUCCC 6643 GGGAAGUGGGAUGGCAGCA 6644 CGGGUUCCCUUUUCCUAAA 6645 UUUAGGAAAAGGGAACCCG 6646 AGCUGCAGCUUAUGGCUUC 6647 GAAGCCAUAAGCUGCAGCU 6648 GCUGCAGCUUAUGGCUUCU 6649 AGAAGCCAUAAGCUGCAGC 6650 CUGCAGCUUAUGGCUUCUC 6651 GAGAAGCCAUAAGCUGCAG 6652 UGCAGCUUAUGGCUUCUCC 6653 GGAGAAGCCAUAAGCUGCA 6654 GCAGCUUAUGGCUUCUCCA 6655 UGGAGAAGCCAUAAGCUGC 6656 CAGCUUAUGGCUUCUCCAG 6657 CUGGAGAAGCCAUAAGCUG 6658 AGCUUAUGGCUUCUCCAGU 6659 ACUGGAGAAGCCAUAAGCU 6660 GCUUAUGGCUUCUCCAGUA 6661 UACUGGAGAAGCCAUAAGC 6662 CUUAUGGCUUCUCCAGUAG 6663 CUACUGGAGAAGCCAUAAG 6664 UUAUGGCUUCUCCAGUAGG 6665 CCUACUGGAGAAGCCAUAA 6666 UAUGGCUUCUCCAGUAGGU 6667 ACCUACUGGAGAAGCCAUA 6668 AUGGCUUCUCCAGUAGGUG 6669 CACCUACUGGAGAAGCCAU 6670 UGGCUUCUCCAGUAGGUGG 6671 CCACCUACUGGAGAAGCCA 6672 GGCUUCUCCAGUAGGUGGC 6673 GCCACCUACUGGAGAAGCC 6674 GCUUCUCCAGUAGGUGGCA 6675 UGCCACCUACUGGAGAAGC 6676 CUUCUCCAGUAGGUGGCAG 6677 CUGCCACCUACUGGAGAAG 6678 UUCUCCAGUAGGUGGCAGC 6679 GCUGCCACCUACUGGAGAA 6680 UCUCCAGUAGGUGGCAGCA 6681 UGCUGCCACCUACUGGAGA 6682 CUCCAGUAGGUGGCAGCAC 6683 GUGCUGCCACCUACUGGAG 6684 ACACCAGAAGUCACAUUUC 6685 GAAAUGUGACUUCUGGUGU 6686 GAAGUCACAUUUCAUCCUU 6687 AAGGAUGAAAUGUGACUUC 6688 AAGUCACAUUUCAUCCUUU 6689 AAAGGAUGAAAUGUGACUU 6690 AGUCACAUUUCAUCCUUUU 6691 AAAAGGAUGAAAUGUGACU 6692 UUUCAUCCUUUUACAUGGU 6693 ACCAUGUAAAAGGAUGAAA 6694 UUCAUCCUUUUACAUGGUU 6695 AACCAUGUAAAAGGAUGAA 6696 UCAUCCUUUUACAUGGUUC 6697 GAACCAUGUAAAAGGAUGA 6698 CAUCCUUUUACAUGGUUCC 6699 GGAACCAUGUAAAAGGAUG 6700 UGGUUCCCAUCUACCCUCA 6701 UGAGGGUAGAUGGGAACCA 6702 GGUUCCCAUCUACCCUCAC 6703 GUGAGGGUAGAUGGGAACC 6704 GUUCCCAUCUACCCUCACA 6705 UGUGAGGGUAGAUGGGAAC 6706 GGCAAUUCUUCCUCCAGGA 6707 UCCUGGAGGAAGAAUUGCC 6708 GCAAUUCUUCCUCCAGGAC 6709 GUCCUGGAGGAAGAAUUGC 6710 CAAUUCUUCCUCCAGGACC 6711 GGUCCUGGAGGAAGAAUUG 6712 AAUUCUUCCUCCAGGACCC 6713 GGGUCCUGGAGGAAGAAUU 6714 CCCUUGGACUUUGCCCUUC 6715 GAAGGGCAAAGUCCAAGGG 6716 CCUUGGACUUUGCCCUUCU 6717 AGAAGGGCAAAGUCCAAGG 6718 CUUGGACUUUGCCCUUCUU 6719 AAGAAGGGCAAAGUCCAAG 6720 UUGGACUUUGCCCUUCUUA 6721 UAAGAAGGGCAAAGUCCAA 6722 UGGACUUUGCCCUUCUUAC 6723 GUAAGAAGGGCAAAGUCCA 6724 GGACUUUGCCCUUCUUACU 6725 AGUAAGAAGGGCAAAGUCC 6726 UUUGCCCUUCUUACUGGCC 6727 GGCCAGUAAGAAGGGCAAA 6728 UUGCCCUUCUUACUGGCCA 6729 UGGCCAGUAAGAAGGGCAA 6730 UGCCCUUCUUACUGGCCAG 6731 CUGGCCAGUAAGAAGGGCA 6732 UCUUACUGGCCAGGCAGGG 6733 CCCUGCCUGGCCAGUAAGA 6734 GGCCAGAGUCCAGGCUUGA 6735 UCAAGCCUGGACUCUGGCC 6736 GCCAGAGUCCAGGCUUGAC 6737 GUCAAGCCUGGACUCUGGC 6738 GUCCAGGCUUGACUCAUUC 6739 GAAUGAGUCAAGCCUGGAC 6740 AGGCUUGACUCAUUCCCAC 6741 GUGGGAAUGAGUCAAGCCU 6742 GACUCAUUCCCACCUUGUC 6743 GACAAGGUGGGAAUGAGUC 6744 ACUCAUUCCCACCUUGUCC 6745 GGACAAGGUGGGAAUGAGU 6746 UCAUUCCCACCUUGUCCUG 6747 CAGGACAAGGUGGGAAUGA 6748 CACCUUGUCCUGGGCUGAG 6749 CUCAGCCCAGGACAAGGUG 6750 ACCACCCAGCCCAGAAGUU 6751 AACUUCUGGGCUGGGUGGU 6752 CCACCCAGCCCAGAAGUUC 6753 GAACUUCUGGGCUGGGUGG 6754 CACCCAGCCCAGAAGUUCC 6755 GGAACUUCUGGGCUGGGUG 6756 ACCCAGCCCAGAAGUUCCA 6757 UGGAACUUCUGGGCUGGGU 6758 CCAGAAGUUCCAGGGAAGG 6759 CCUUCCCUGGAACUUCUGG 6760 CAGAAGUUCCAGGGAAGGA 6761 UCCUUCCCUGGAACUUCUG 6762 AACUCUCCGGUCCACCAUG 6763 CAUGGUGGACCGGAGAGUU 6764 ACUCUCCGGUCCACCAUGG 6765 CCAUGGUGGACCGGAGAGU 6766 CACCAUGGAGUACCUCUCA 6767 UGAGAGGUACUCCAUGGUG 6768 ACCAUGGAGUACCUCUCAG 6769 CUGAGAGGUACUCCAUGGU 6770 UGGAGUACCUCUCAGCUCU 6771 AGAGCUGAGAGGUACUCCA 6772 GGAGUACCUCUCAGCUCUG 6773 CAGAGCUGAGAGGUACUCC 6774 GAGUACCUCUCAGCUCUGA 6775 UCAGAGCUGAGAGGUACUC 6776 AGUACCUCUCAGCUCUGAA 6777 UUCAGAGCUGAGAGGUACU 6778 CCAGUGACUUACUCAGGUG 6779 CACCUGAGUAAGUCACUGG 6780 CAGUGACUUACUCAGGUGA 6781 UCACCUGAGUAAGUCACUG 6782 AGUGACUUACUCAGGUGAC 6783 GUCACCUGAGUAAGUCACU 6784 GUGACUUACUCAGGUGACU 6785 AGUCACCUGAGUAAGUCAC 6786 UGACUUACUCAGGUGACUG 6787 CAGUCACCUGAGUAAGUCA 6788 GACUUACUCAGGUGACUGC 6789 GCAGUCACCUGAGUAAGUC 6790 ACUUACUCAGGUGACUGCU 6791 AGCAGUCACCUGAGUAAGU 6792 CUUACUCAGGUGACUGCUA 6793 UAGCAGUCACCUGAGUAAG 6794 UUACUCAGGUGACUGCUAA 6795 UUAGCAGUCACCUGAGUAA 6796 UACUCAGGUGACUGCUAAC 6797 GUUAGCAGUCACCUGAGUA 6798 ACUCAGGUGACUGCUAACC 6799 GGUUAGCAGUCACCUGAGU 6800 CUCAGGUGACUGCUAACCC 6801 GGGUUAGCAGUCACCUGAG 6802 GGUGACUGCUAACCCUCCG 6803 CGGAGGGUUAGCAGUCACC 6804 GUGACUGCUAACCCUCCGC 6805 GCGGAGGGUUAGCAGUCAC 6806 UGACUGCUAACCCUCCGCU 6807 AGCGGAGGGUUAGCAGUCA 6808 GACUGCUAACCCUCCGCUC 6809 GAGCGGAGGGUUAGCAGUC 6810 ACUGCUAACCCUCCGCUCU 6811 AGAGCGGAGGGUUAGCAGU 6812 CUGCUAACCCUCCGCUCUA 6813 UAGAGCGGAGGGUUAGCAG 6814 UGCUAACCCUCCGCUCUAC 6815 GUAGAGCGGAGGGUUAGCA 6816 AACCCUCCGCUCUACCCUC 6817 GAGGGUAGAGCGGAGGGUU 6818 ACUCCACAGUGGGCUUGUC 6819 GACAAGCCCACUGUGGAGU 6820 CUCCACAGUGGGCUUGUCA 6821 UGACAAGCCCACUGUGGAG 6822 UCCACAGUGGGCUUGUCAA 6823 UUGACAAGCCCACUGUGGA 6824 CCACAGUGGGCUUGUCAAG 6825 CUUGACAAGCCCACUGUGG 6826 GUCAAGCUCCUGAGCCACC 6827 GGUGGCUCAGGAGCUUGAC 6828 CCAUGGUCUCUCCCUCAUC 6829 GAUGAGGGAGAGACCAUGG 6830 CAUGGUCUCUCCCUCAUCC 6831 GGAUGAGGGAGAGACCAUG 6832 AUGGUCUCUCCCUCAUCCC 6833 GGGAUGAGGGAGAGACCAU 6834 UCUCUCCCUCAUCCCUAAU 6835 AUUAGGGAUGAGGGAGAGA 6836 CUCUCCCUCAUCCCUAAUC 6837 GAUUAGGGAUGAGGGAGAG 6838 UCUCCCUCAUCCCUAAUCG 6839 CGAUUAGGGAUGAGGGAGA 6840 CUCCCUCAUCCCUAAUCGA 6841 UCGAUUAGGGAUGAGGGAG 6842 UCCCUCAUCCCUAAUCGAU 6843 AUCGAUUAGGGAUGAGGGA 6844 CCCUCAUCCCUAAUCGAUA 6845 UAUCGAUUAGGGAUGAGGG 6846 CCUCAUCCCUAAUCGAUAA 6847 UUAUCGAUUAGGGAUGAGG 6848 CUCAUCCCUAAUCGAUAAA 6849 UUUAUCGAUUAGGGAUGAG 6850 AACCUAGAUCUCUCCCUCC 6851 GGAGGGAGAGAUCUAGGUU 6852 ACCUAGAUCUCUCCCUCCC 6853 GGGAGGGAGAGAUCUAGGU 6854 CUAGAUCUCUCCCUCCCUA 6855 UAGGGAGGGAGAGAUCUAG 6856 UAGAUCUCUCCCUCCCUAG 6857 CUAGGGAGGGAGAGAUCUA 6858 AGAUCUCUCCCUCCCUAGC 6859 GCUAGGGAGGGAGAGAUCU 6860 GAUCUCUCCCUCCCUAGCC 6861 GGCUAGGGAGGGAGAGAUC 6862 AUCUCUCCCUCCCUAGCCC 6863 GGGCUAGGGAGGGAGAGAU 6864 UAGCCCUCUAGCCACUCUA 6865 UAGAGUGGCUAGAGGGCUA 6866 AGCCCUCUAGCCACUCUAC 6867 GUAGAGUGGCUAGAGGGCU 6868 CUCUAGCCACUCUACCCUC 6869 GAGGGUAGAGUGGCUAGAG 6870 UCUAGCCACUCUACCCUCA 6871 UGAGGGUAGAGUGGCUAGA 6872 CUAGCCACUCUACCCUCAU 6873 AUGAGGGUAGAGUGGCUAG 6874 UAGCCACUCUACCCUCAUC 6875 GAUGAGGGUAGAGUGGCUA 6876 AGCCACUCUACCCUCAUCA 6877 UGAUGAGGGUAGAGUGGCU 6878 GCCACUCUACCCUCAUCAU 6879 AUGAUGAGGGUAGAGUGGC 6880 CCACUCUACCCUCAUCAUG 6881 CAUGAUGAGGGUAGAGUGG 6882 CACUCUACCCUCAUCAUGC 6883 GCAUGAUGAGGGUAGAGUG 6884 ACUCUACCCUCAUCAUGCC 6885 GGCAUGAUGAGGGUAGAGU 6886 CUCUACCCUCAUCAUGCCC 6887 GGGCAUGAUGAGGGUAGAG 6888 UCUACCCUCAUCAUGCCCU 6889 AGGGCAUGAUGAGGGUAGA 6890 CUACCCUCAUCAUGCCCUU 6891 AAGGGCAUGAUGAGGGUAG 6892 UACCCUCAUCAUGCCCUUU 6893 AAAGGGCAUGAUGAGGGUA 6894 ACCCUCAUCAUGCCCUUUA 6895 UAAAGGGCAUGAUGAGGGU 6896 CCCUCAUCAUGCCCUUUAC 6897 GUAAAGGGCAUGAUGAGGG 6898 CUCAUCAUGCCCUUUACAC 6899 GUGUAAAGGGCAUGAUGAG 6900 UCAUCAUGCCCUUUACACU 6901 AGUGUAAAGGGCAUGAUGA 6902 CCCUUCUUGACUUUUCUUC 6903 GAAGAAAAGUCAAGAAGGG 6904 CUUCUUGACUUUUCUUCUC 6905 GAGAAGAAAAGUCAAGAAG 6906 GACUUUUCUUCUCAACUAC 6907 GUAGUUGAGAAGAAAAGUC 6908 ACUUUUCUUCUCAACUACC 6909 GGUAGUUGAGAAGAAAAGU 6910 CUUUUCUUCUCAACUACCA 6911 UGGUAGUUGAGAAGAAAAG 6912 UUUUCUUCUCAACUACCAG 6913 CUGGUAGUUGAGAAGAAAA 6914 UAUCUAAUAUAAGCUCGGA 6915 UCCGAGCUUAUAUUAGAUA 6916 AUCUAAUAUAAGCUCGGAG 6917 CUCCGAGCUUAUAUUAGAU 6918 UCUAAUAUAAGCUCGGAGU 6919 ACUCCGAGCUUAUAUUAGA 6920 CUAAUAUAAGCUCGGAGUU 6921 AACUCCGAGCUUAUAUUAG 6922 UAAUAUAAGCUCGGAGUUU 6923 AAACUCCGAGCUUAUAUUA 6924 AAUAUAAGCUCGGAGUUUG 6925 CAAACUCCGAGCUUAUAUU 6926 AUAUAAGCUCGGAGUUUGG 6927 CCAAACUCCGAGCUUAUAU 6928 UAUAAGCUCGGAGUUUGGA 6929 UCCAAACUCCGAGCUUAUA 6930 AUAAGCUCGGAGUUUGGAC 6931 GUCCAAACUCCGAGCUUAU 6932 UAAGCUCGGAGUUUGGACG 6933 CGUCCAAACUCCGAGCUUA 6934 AAGCUCGGAGUUUGGACGG 6935 CCGUCCAAACUCCGAGCUU 6936 AGCUCGGAGUUUGGACGGA 6937 UCCGUCCAAACUCCGAGCU 6938 GCUCGGAGUUUGGACGGAG 6939 CUCCGUCCAAACUCCGAGC 6940 CUCGGAGUUUGGACGGAGG 6941 CCUCCGUCCAAACUCCGAG 6942 UCGGAGUUUGGACGGAGGG 6943 CCCUCCGUCCAAACUCCGA 6944 CGGAGUUUGGACGGAGGGU 6945 ACCCUCCGUCCAAACUCCG 6946 UUUGGACGGAGGGUCUGGA 6947 UCCAGACCCUCCGUCCAAA 6948 CCCAGCGACCUUUCCGUGU 6949 ACACGGAAAGGUCGCUGGG 6950 CCAGCGACCUUUCCGUGUC 6951 GACACGGAAAGGUCGCUGG 6952 CAGCGACCUUUCCGUGUCU 6953 AGACACGGAAAGGUCGCUG 6954 AGCGACCUUUCCGUGUCUG 6955 CAGACACGGAAAGGUCGCU 6956 GCGACCUUUCCGUGUCUGU 6957 ACAGACACGGAAAGGUCGC 6958 CGACCUUUCCGUGUCUGUG 6959 CACAGACACGGAAAGGUCG 6960 CUUUCCGUGUCUGUGAUCA 6961 UGAUCACAGACACGGAAAG 6962 UUUCCGUGUCUGUGAUCAC 6963 GUGAUCACAGACACGGAAA 6964 UUCCGUGUCUGUGAUCACA 6965 UGUGAUCACAGACACGGAA 6966 AAGGCCUGACAGCUGCCAC 6967 GUGGCAGCUGUCAGGCCUU 6968 GCCAGGAGCUGCUAGCCAA 6969 UUGGCUAGCAGCUCCUGGC 6970 CCAGGAGCUGCUAGCCAAA 6971 UUUGGCUAGCAGCUCCUGG 6972 GAGCUGCUAGCCAAAGUAA 6973 UUACUUUGGCUAGCAGCUC 6974 AGCUGCUAGCCAAAGUAAG 6975 CUUACUUUGGCUAGCAGCU 6976 GCUGCUAGCCAAAGUAAGU 6977 ACUUACUUUGGCUAGCAGC 6978 CUGCUAGCCAAAGUAAGUA 6979 UACUUACUUUGGCUAGCAG 6980 UGCUAGCCAAAGUAAGUAG 6981 CUACUUACUUUGGCUAGCA 6982 GCUAGCCAAAGUAAGUAGG 6983 CCUACUUACUUUGGCUAGC 6984 UAGCCAAAGUAAGUAGGCC 6985 GGCCUACUUACUUUGGCUA 6986 AGCCAAAGUAAGUAGGCCA 6987 UGGCCUACUUACUUUGGCU 6988 GCCAAAGUAAGUAGGCCAA 6989 UUGGCCUACUUACUUUGGC 6990 CCAAAGUAAGUAGGCCAAG 6991 CUUGGCCUACUUACUUUGG 6992 CAAAGUAAGUAGGCCAAGU 6993 ACUUGGCCUACUUACUUUG 6994 AAAGUAAGUAGGCCAAGUU 6995 AACUUGGCCUACUUACUUU 6996 AAGUAAGUAGGCCAAGUUC 6997 GAACUUGGCCUACUUACUU 6998 AGUAAGUAGGCCAAGUUCC 6999 GGAACUUGGCCUACUUACU 7000 GUAAGUAGGCCAAGUUCCU 7001 AGGAACUUGGCCUACUUAC 7002 UAAGUAGGCCAAGUUCCUC 7003 GAGGAACUUGGCCUACUUA 7004 UAGGCCAAGUUCCUCGGUU 7005 AACCGAGGAACUUGGCCUA 7006 AGGCCAAGUUCCUCGGUUC 7007 GAACCGAGGAACUUGGCCU 7008 GGCCAAGUUCCUCGGUUCC 7009 GGAACCGAGGAACUUGGCC 7010 GCCAAGUUCCUCGGUUCCU 7011 AGGAACCGAGGAACUUGGC 7012 CCAAGUUCCUCGGUUCCUA 7013 UAGGAACCGAGGAACUUGG 7014 CAAGUUCCUCGGUUCCUAU 7015 AUAGGAACCGAGGAACUUG 7016 AAGUUCCUCGGUUCCUAUA 7017 UAUAGGAACCGAGGAACUU 7018 AGUUCCUCGGUUCCUAUAG 7019 CUAUAGGAACCGAGGAACU 7020 GUUCCUCGGUUCCUAUAGC 7021 GCUAUAGGAACCGAGGAAC 7022 UUCCUCGGUUCCUAUAGCA 7023 UGCUAUAGGAACCGAGGAA 7024 UCCUCGGUUCCUAUAGCAG 7025 CUGCUAUAGGAACCGAGGA 7026 CAGUGGCAACUUGUGAUGA 7027 UCAUCACAAGUUGCCACUG 7028 AGUGGCAACUUGUGAUGAU 7029 AUCAUCACAAGUUGCCACU 7030 GUGGCAACUUGUGAUGAUG 7031 CAUCAUCACAAGUUGCCAC 7032 GGCAACUUGUGAUGAUGGA 7033 UCCAUCAUCACAAGUUGCC 7034 ACUUGUGAUGAUGGAGCAG 7035 CUGCUCCAUCAUCACAAGU 7036 CUUGUGAUGAUGGAGCAGA 7037 UCUGCUCCAUCAUCACAAG 7038 GUGAUGAUGGAGCAGAGGG 7039 CCCUCUGCUCCAUCAUCAC 7040 UGAUGAUGGAGCAGAGGGC 7041 GCCCUCUGCUCCAUCAUCA 7042 UGGAGCAGAGGGCUGAAGU 7043 ACUUCAGCCCUCUGCUCCA 7044 GGAGCAGAGGGCUGAAGUC 7045 GACUUCAGCCCUCUGCUCC 7046 GAGCAGAGGGCUGAAGUCA 7047 UGACUUCAGCCCUCUGCUC 7048 CUAAAAGCAGCGGAGUGGG 7049 CCCACUCCGCUGCUUUUAG 7050 UAAAAGCAGCGGAGUGGGC 7051 GCCCACUCCGCUGCUUUUA 7052 AAAAGCAGCGGAGUGGGCC 7053 GGCCCACUCCGCUGCUUUU 7054 AAAGCAGCGGAGUGGGCCU 7055 AGGCCCACUCCGCUGCUUU 7056 AAGCAGCGGAGUGGGCCUA 7057 UAGGCCCACUCCGCUGCUU 7058 AGCAGCGGAGUGGGCCUAA 7059 UUAGGCCCACUCCGCUGCU 7060 GCAGCGGAGUGGGCCUAAU 7061 AUUAGGCCCACUCCGCUGC 7062 CAGCGGAGUGGGCCUAAUG 7063 CAUUAGGCCCACUCCGCUG 7064 AGCGGAGUGGGCCUAAUGA 7065 UCAUUAGGCCCACUCCGCU 7066 GCGGAGUGGGCCUAAUGAG 7067 CUCAUUAGGCCCACUCCGC 7068 AGUGGGCCUAAUGAGCUCU 7069 AGAGCUCAUUAGGCCCACU 7070 GUGGGCCUAAUGAGCUCUG 7071 CAGAGCUCAUUAGGCCCAC 7072 UGGGCCUAAUGAGCUCUGG 7073 CCAGAGCUCAUUAGGCCCA 7074 GGGCCUAAUGAGCUCUGGU 7075 ACCAGAGCUCAUUAGGCCC 7076 GGCCUAAUGAGCUCUGGUC 7077 GACCAGAGCUCAUUAGGCC 7078 GCCUAAUGAGCUCUGGUCA 7079 UGACCAGAGCUCAUUAGGC 7080 CCUAAUGAGCUCUGGUCAA 7081 UUGACCAGAGCUCAUUAGG 7082 CUAAUGAGCUCUGGUCAAU 7083 AUUGACCAGAGCUCAUUAG 7084 UAAUGAGCUCUGGUCAAUU 7085 AAUUGACCAGAGCUCAUUA 7086 AAUGAGCUCUGGUCAAUUU 7087 AAAUUGACCAGAGCUCAUU 7088 AUGAGCUCUGGUCAAUUUG 7089 CAAAUUGACCAGAGCUCAU 7090 UGAGCUCUGGUCAAUUUGU 7091 ACAAAUUGACCAGAGCUCA 7092 CUGGUCAAUUUGUUCAUUU 7093 AAAUGAACAAAUUGACCAG 7094 CAAUUUGUUCAUUUUCCAC 7095 GUGGAAAAUGAACAAAUUG 7096 AGUGAGCUUUUCUAUGGGA 7097 UCCCAUAGAAAAGCUCACU 7098 AGCUUUUCUAUGGGAGCAG 7099 CUGCUCCCAUAGAAAAGCU 7100 GAAUUCAGAAGCUAGUAUG 7101 CAUACUAGCUUCUGAAUUC 7102 AUUCAGAAGCUAGUAUGGA 7103 UCCAUACUAGCUUCUGAAU 7104 UUCAGAAGCUAGUAUGGAA 7105 UUCCAUACUAGCUUCUGAA 7106 AAAGGUGAUUUGUGUGACA 7107 UGUCACACAAAUCACCUUU 7108 AUUCUGAUUCUGCCACUUC 7109 GAAGUGGCAGAAUCAGAAU 7110 AUUCUGCCACUUCCUGCCU 7111 AGGCAGGAAGUGGCAGAAU 7112 GCCACUUCCUGCCUGUCAA 7113 UUGACAGGCAGGAAGUGGC 7114 CCACUUCCUGCCUGUCAAA 7115 UUUGACAGGCAGGAAGUGG 7116 AACCUUGGGAAGUUGUUCA 7117 UGAACAACUUCCCAAGGUU 7118 ACCUUGGGAAGUUGUUCAA 7119 UUGAACAACUUCCCAAGGU 7120 CCUUGGGAAGUUGUUCAAC 7121 GUUGAACAACUUCCCAAGG 7122 GGGAAGUUGUUCAACCUAC 7123 GUAGGUUGAACAACUUCCC 7124 GGAAGUUGUUCAACCUACC 7125 GGUAGGUUGAACAACUUCC 7126 GAAGUUGUUCAACCUACCA 7127 UGGUAGGUUGAACAACUUC 7128 AAGUUGUUCAACCUACCAA 7129 UUGGUAGGUUGAACAACUU 7130 AGUUGUUCAACCUACCAAA 7131 UUUGGUAGGUUGAACAACU 7132 GUUGUUCAACCUACCAAAA 7133 UUUUGGUAGGUUGAACAAC 7134 GCAAUAAUAAUACAUCACC 7135 GGUGAUGUAUUAUUAUUGC 7136 AUAAUAAUACAUCACCUCC 7137 GGAGGUGAUGUAUUAUUAU 7138 UAAUACAUCACCUCCUAGG 7139 CCUAGGAGGUGAUGUAUUA 7140 AAUACAUCACCUCCUAGGG 7141 CCCUAGGAGGUGAUGUAUU 7142 AUACAUCACCUCCUAGGGU 7143 ACCCUAGGAGGUGAUGUAU 7144 UACAUCACCUCCUAGGGUU 7145 AACCCUAGGAGGUGAUGUA 7146 ACAUCACCUCCUAGGGUUG 7147 CAACCCUAGGAGGUGAUGU 7148 AAAGGAGUAAGAGGAUAAU 7149 AUUAUCCUCUUACUCCUUU 7150 AAGGAGUAAGAGGAUAAUG 7151 CAUUAUCCUCUUACUCCUU 7152 AGUAAGAGGAUAAUGUAGG 7153 CCUACAUUAUCCUCUUACU 7154 GUAAGAGGAUAAUGUAGGU 7155 ACCUACAUUAUCCUCUUAC 7156 UAAGAGGAUAAUGUAGGUA 7157 UACCUACAUUAUCCUCUUA 7158 AAGAGGAUAAUGUAGGUAA 7159 UUACCUACAUUAUCCUCUU 7160 AGAGGAUAAUGUAGGUAAA 7161 UUUACCUACAUUAUCCUCU 7162 GAGGAUAAUGUAGGUAAAG 7163 CUUUACCUACAUUAUCCUC 7164 GGAUAAUGUAGGUAAAGUC 7165 GACUUUACCUACAUUAUCC 7166 AUAAUGUAGGUAAAGUCCU 7167 AGGACUUUACCUACAUUAU 7168 GUAGGUAAAGUCCUCAUAC 7169 GUAUGAGGACUUUACCUAC 7170 GUAAAGUCCUCAUACCUGG 7171 CCAGGUAUGAGGACUUUAC 7172 UAAAGUCCUCAUACCUGGC 7173 GCCAGGUAUGAGGACUUUA 7174 AAAGUCCUCAUACCUGGCA 7175 UGCCAGGUAUGAGGACUUU 7176 AAGUCCUCAUACCUGGCAC 7177 GUGCCAGGUAUGAGGACUU 7178 AGUCCUCAUACCUGGCACA 7179 UGUGCCAGGUAUGAGGACU 7180 GUCCUCAUACCUGGCACAG 7181 CUGUGCCAGGUAUGAGGAC 7182 UCCUCAUACCUGGCACAGA 7183 UCUGUGCCAGGUAUGAGGA 7184 UCUUGAGGGUGUGGGAAGU 7185 ACUUCCCACACCCUCAAGA 7186 CUUGAGGGUGUGGGAAGUG 7187 CACUUCCCACACCCUCAAG 7188 UUGAGGGUGUGGGAAGUGA 7189 UCACUUCCCACACCCUCAA 7190 UGAGGGUGUGGGAAGUGAG 7191 CUCACUUCCCACACCCUCA 7192 AGGGUGUGGGAAGUGAGGU 7193 ACCUCACUUCCCACACCCU 7194 GGGUGUGGGAAGUGAGGUG 7195 CACCUCACUUCCCACACCC 7196 GGGAAGUGAGGUGCAGCAU 7197 AUGCUGCACCUCACUUCCC 7198 GGAAGUGAGGUGCAGCAUU 7199 AAUGCUGCACCUCACUUCC 7200 GAAGUGAGGUGCAGCAUUG 7201 CAAUGCUGCACCUCACUUC 7202 AAGUGAGGUGCAGCAUUGU 7203 ACAAUGCUGCACCUCACUU 7204 AGUGAGGUGCAGCAUUGUA 7205 UACAAUGCUGCACCUCACU 7206 GUGAGGUGCAGCAUUGUAG 7207 CUACAAUGCUGCACCUCAC 7208 UGAGGUGCAGCAUUGUAGA 7209 UCUACAAUGCUGCACCUCA 7210 GAGGUGCAGCAUUGUAGAU 7211 AUCUACAAUGCUGCACCUC 7212 AGGUGCAGCAUUGUAGAUA 7213 UAUCUACAAUGCUGCACCU 7214 GGUGCAGCAUUGUAGAUAA 7215 UUAUCUACAAUGCUGCACC 7216 GUGCAGCAUUGUAGAUAAG 7217 CUUAUCUACAAUGCUGCAC 7218 UGCAGCAUUGUAGAUAAGA 7219 UCUUAUCUACAAUGCUGCA 7220 GCAUUGUAGAUAAGACAGA 7221 UCUGUCUUAUCUACAAUGC 7222 CAUUGUAGAUAAGACAGAA 7223 UUCUGUCUUAUCUACAAUG 7224 AUUGUAGAUAAGACAGAAG 7225 CUUCUGUCUUAUCUACAAU 7226 AUAAGACAGAAGGGUGGAC 7227 GUCCACCCUUCUGUCUUAU 7228 UAAGACAGAAGGGUGGACU 7229 AGUCCACCCUUCUGUCUUA 7230 AACCUGGCUUGCUUUCCAA 7231 UUGGAAAGCAAGCCAGGUU 7232 CCUGGCUUGCUUUCCAAUU 7233 AAUUGGAAAGCAAGCCAGG 7234 ACCAGAAGUGACUUGGAGG 7235 CCUCCAAGUCACUUCUGGU 7236 CCAGAAGUGACUUGGAGGG 7237 CCCUCCAAGUCACUUCUGG 7238 AGAUGCCAAUGACAUGGUA 7239 UACCAUGUCAUUGGCAUCU 7240 GAUGCCAAUGACAUGGUAG 7241 CUACCAUGUCAUUGGCAUC 7242 AUGCCAAUGACAUGGUAGG 7243 CCUACCAUGUCAUUGGCAU 7244 CAAUGACAUGGUAGGAGCA 7245 UGCUCCUACCAUGUCAUUG 7246 AAUGACAUGGUAGGAGCAA 7247 UUGCUCCUACCAUGUCAUU 7248 AUGACAUGGUAGGAGCAAA 7249 UUUGCUCCUACCAUGUCAU 7250 UGACAUGGUAGGAGCAAAG 7251 CUUUGCUCCUACCAUGUCA 7252 GACAUGGUAGGAGCAAAGA 7253 UCUUUGCUCCUACCAUGUC 7254 AAAAGGUCAGCCUCUAGCU 7255 AGCUAGAGGCUGACCUUUU 7256 AAAGGUCAGCCUCUAGCUA 7257 UAGCUAGAGGCUGACCUUU 7258 AGGUCAGCCUCUAGCUAGG 7259 CCUAGCUAGAGGCUGACCU 7260 GGUCAGCCUCUAGCUAGGA 7261 UCCUAGCUAGAGGCUGACC 7262 GUCAGCCUCUAGCUAGGAU 7263 AUCCUAGCUAGAGGCUGAC 7264 CAGCCUCUAGCUAGGAUCC 7265 GGAUCCUAGCUAGAGGCUG 7266 AGCCUCUAGCUAGGAUCCC 7267 GGGAUCCUAGCUAGAGGCU 7268 AGAGCUGCAACCUUUAGGA 7269 UCCUAAAGGUUGCAGCUCU 7270 GAGCUGCAACCUUUAGGAG 7271 CUCCUAAAGGUUGCAGCUC 7272 AGCUGCAACCUUUAGGAGG 7273 CCUCCUAAAGGUUGCAGCU 7274 UUUAGGAGGUAUCAAAGUG 7275 CACUUUGAUACCUCCUAAA 7276 UUAGGAGGUAUCAAAGUGC 7277 GCACUUUGAUACCUCCUAA 7278 UAGGAGGUAUCAAAGUGCC 7279 GGCACUUUGAUACCUCCUA 7280 GUCAAAGUGGGACAUCGAC 7281 GUCGAUGUCCCACUUUGAC 7282 CAUCGACCAAUGUCUAGAG 7283 CUCUAGACAUUGGUCGAUG 7284 AUCGACCAAUGUCUAGAGC 7285 GCUCUAGACAUUGGUCGAU 7286 ACCAAUGUCUAGAGCCAAC 7287 GUUGGCUCUAGACAUUGGU 7288 CAAUGUCUAGAGCCAACUG 7289 CAGUUGGCUCUAGACAUUG 7290 AAUGUCUAGAGCCAACUGA 7291 UCAGUUGGCUCUAGACAUU 7292 AUGUCUAGAGCCAACUGAU 7293 AUCAGUUGGCUCUAGACAU 7294 UGUCUAGAGCCAACUGAUG 7295 CAUCAGUUGGCUCUAGACA 7296 GUCUAGAGCCAACUGAUGG 7297 CCAUCAGUUGGCUCUAGAC 7298 UCUAGAGCCAACUGAUGGA 7299 UCCAUCAGUUGGCUCUAGA 7300 CUAGAGCCAACUGAUGGAU 7301 AUCCAUCAGUUGGCUCUAG 7302 UAGAGCCAACUGAUGGAUG 7303 CAUCCAUCAGUUGGCUCUA 7304 AGAGCCAACUGAUGGAUGU 7305 ACAUCCAUCAGUUGGCUCU 7306 GAGCCAACUGAUGGAUGUU 7307 AACAUCCAUCAGUUGGCUC 7308 AACUGAUGGAUGUUGGGCA 7309 UGCCCAACAUCCAUCAGUU 7310 UGGAUGUUGGGCAGCUAAA 7311 UUUAGCUGCCCAACAUCCA 7312 GGAUGUUGGGCAGCUAAAG 7313 CUUUAGCUGCCCAACAUCC 7314 GAUGUUGGGCAGCUAAAGA 7315 UCUUUAGCUGCCCAACAUC 7316 UUGGGCAGCUAAAGAGGGA 7317 UCCCUCUUUAGCUGCCCAA 7318 UGGGCAGCUAAAGAGGGAA 7319 UUCCCUCUUUAGCUGCCCA 7320 GGGCAGCUAAAGAGGGAAG 7321 CUUCCCUCUUUAGCUGCCC 7322 GGCAGCUAAAGAGGGAAGG 7323 CCUUCCCUCUUUAGCUGCC 7324 GCAGCUAAAGAGGGAAGGG 7325 CCCUUCCCUCUUUAGCUGC 7326 GGGCAUGGGAUAAGACCUG 7327 CAGGUCUUAUCCCAUGCCC 7328 GGCAUGGGAUAAGACCUGC 7329 GCAGGUCUUAUCCCAUGCC 7330 GCAUGGGAUAAGACCUGCC 7331 GGCAGGUCUUAUCCCAUGC 7332 CAUGGGAUAAGACCUGCCC 7333 GGGCAGGUCUUAUCCCAUG 7334 AUGGGAUAAGACCUGCCCU 7335 AGGGCAGGUCUUAUCCCAU 7336 UGGGAUAAGACCUGCCCUU 7337 AAGGGCAGGUCUUAUCCCA 7338 GGGAUAAGACCUGCCCUUC 7339 GAAGGGCAGGUCUUAUCCC 7340 GGAUAAGACCUGCCCUUCU 7341 AGAAGGGCAGGUCUUAUCC 7342 AGACCUGCCCUUCUUGCUU 7343 AAGCAAGAAGGGCAGGUCU 7344 GACCUGCCCUUCUUGCUUC 7345 GAAGCAAGAAGGGCAGGUC 7346 CCUGCCCUUCUUGCUUCUU 7347 AAGAAGCAAGAAGGGCAGG 7348 CUGCCCUUCUUGCUUCUUG 7349 CAAGAAGCAAGAAGGGCAG 7350 UGCCCUUCUUGCUUCUUGC 7351 GCAAGAAGCAAGAAGGGCA 7352 UCUUGCUUCUUGCCAUUGG 7353 CCAAUGGCAAGAAGCAAGA 7354 CUUGCUUCUUGCCAUUGGG 7355 CCCAAUGGCAAGAAGCAAG 7356 UUGCUUCUUGCCAUUGGGC 7357 GCCCAAUGGCAAGAAGCAA 7358 CCAUUGGGCAGGCAUUGGA 7359 UCCAAUGCCUGCCCAAUGG 7360 CAUUGGGCAGGCAUUGGAG 7361 CUCCAAUGCCUGCCCAAUG 7362 GACCCUACUGCUGAAUGGA 7363 UCCAUUCAGCAGUAGGGUC 7364 UACUGCUGAAUGGAGUGCU 7365 AGCACUCCAUUCAGCAGUA 7366 ACUGCUGAAUGGAGUGCUA 7367 UAGCACUCCAUUCAGCAGU 7368 CUGCUGAAUGGAGUGCUAA 7369 UUAGCACUCCAUUCAGCAG 7370 UGCUGAAUGGAGUGCUAAC 7371 GUUAGCACUCCAUUCAGCA 7372 GCUGAAUGGAGUGCUAACC 7373 GGUUAGCACUCCAUUCAGC 7374 CUGAAUGGAGUGCUAACCC 7375 GGGUUAGCACUCCAUUCAG 7376 UAACCCUGGUGCUAGAGGA 7377 UCCUCUAGCACCAGGGUUA 7378 AACCCUGGUGCUAGAGGAG 7379 CUCCUCUAGCACCAGGGUU 7380 ACCCUGGUGCUAGAGGAGG 7381 CCUCCUCUAGCACCAGGGU 7382 CCCUGGUGCUAGAGGAGGA 7383 UCCUCCUCUAGCACCAGGG 7384 CCUGGUGCUAGAGGAGGAU 7385 AUCCUCCUCUAGCACCAGG 7386 CUGGUGCUAGAGGAGGAUG 7387 CAUCCUCCUCUAGCACCAG 7388 GGUGCUAGAGGAGGAUGGA 7389 UCCAUCCUCCUCUAGCACC 7390 GUGCUAGAGGAGGAUGGAA 7391 UUCCAUCCUCCUCUAGCAC 7392 CUGCAGUGGACAGUGAGGA 7393 UCCUCACUGUCCACUGCAG 7394 UGCAGUGGACAGUGAGGAC 7395 GUCCUCACUGUCCACUGCA 7396 GCAGUGGACAGUGAGGACU 7397 AGUCCUCACUGUCCACUGC 7398 CAGUGGACAGUGAGGACUU 7399 AAGUCCUCACUGUCCACUG 7400 AGUGGACAGUGAGGACUUC 7401 GAAGUCCUCACUGUCCACU 7402 GUGGACAGUGAGGACUUCU 7403 AGAAGUCCUCACUGUCCAC 7404 UGGACAGUGAGGACUUCUU 7405 AAGAAGUCCUCACUGUCCA 7406 GGACAGUGAGGACUUCUUC 7407 GAAGAAGUCCUCACUGUCC 7408 AGUGAGGACUUCUUCCAGC 7409 GCUGGAAGAAGUCCUCACU 7410 GUGAGGACUUCUUCCAGCU 7411 AGCUGGAAGAAGUCCUCAC 7412 UGAGGACUUCUUCCAGCUG 7413 CAGCUGGAAGAAGUCCUCA 7414 GAGGACUUCUUCCAGCUGC 7415 GCAGCUGGAAGAAGUCCUC 7416 GUGCCUGAUGGUGUUGCAG 7417 CUGCAACACCAUCAGGCAC 7418 GAUGGUGUUGCAGUCUGGU 7419 ACCAGACUGCAACACCAUC 7420 UGGUGUUGCAGUCUGGUCA 7421 UGACCAGACUGCAACACCA 7422 GGUGUUGCAGUCUGGUCAG 7423 CUGACCAGACUGCAACACC 7424 GUGUUGCAGUCUGGUCAGA 7425 UCUGACCAGACUGCAACAC 7426 UGCAGUCUGGUCAGAGCUG 7427 CAGCUCUGACCAGACUGCA 7428 GCAGUCUGGUCAGAGCUGG 7429 CCAGCUCUGACCAGACUGC 7430 CAGUCUGGUCAGAGCUGGA 7431 UCCAGCUCUGACCAGACUG 7432 AGUCUGGUCAGAGCUGGAG 7433 CUCCAGCUCUGACCAGACU 7434 GUCUGGUCAGAGCUGGAGC 7435 GCUCCAGCUCUGACCAGAC 7436 UCUGGUCAGAGCUGGAGCC 7437 GGCUCCAGCUCUGACCAGA 7438 UGGUCAGAGCUGGAGCCCU 7439 AGGGCUCCAGCUCUGACCA 7440 GGUCAGAGCUGGAGCCCUA 7441 UAGGGCUCCAGCUCUGACC 7442 GUCAGAGCUGGAGCCCUAC 7443 GUAGGGCUCCAGCUCUGAC 7444 CAAGGGUAAGAGGCCUAUA 7445 UAUAGGCCUCUUACCCUUG 7446 AAGGGUAAGAGGCCUAUAC 7447 GUAUAGGCCUCUUACCCUU 7448 AGGGUAAGAGGCCUAUACU 7449 AGUAUAGGCCUCUUACCCU 7450 GGGUAAGAGGCCUAUACUG 7451 CAGUAUAGGCCUCUUACCC 7452 GGUAAGAGGCCUAUACUGG 7453 CCAGUAUAGGCCUCUUACC 7454 GUAAGAGGCCUAUACUGGG 7455 CCCAGUAUAGGCCUCUUAC 7456 GGGCUGCUUCCAAUGCCUG 7457 CAGGCAUUGGAAGCAGCCC 7458 GGCUGCUUCCAAUGCCUGU 7459 ACAGGCAUUGGAAGCAGCC 7460 GCUGCUUCCAAUGCCUGUC 7461 GACAGGCAUUGGAAGCAGC 7462 CUGCUUCCAAUGCCUGUCC 7463 GGACAGGCAUUGGAAGCAG 7464 UGCUUCCAAUGCCUGUCCU 7465 AGGACAGGCAUUGGAAGCA 7466 GCUUCCAAUGCCUGUCCUU 7467 AAGGACAGGCAUUGGAAGC 7468 CUUCCAAUGCCUGUCCUUU 7469 AAAGGACAGGCAUUGGAAG 7470 UUCCAAUGCCUGUCCUUUA 7471 UAAAGGACAGGCAUUGGAA 7472 UCCAAUGCCUGUCCUUUAG 7473 CUAAAGGACAGGCAUUGGA 7474 CAAUGCCUGUCCUUUAGAG 7475 CUCUAAAGGACAGGCAUUG 7476 AAUGCCUGUCCUUUAGAGC 7477 GCUCUAAAGGACAGGCAUU 7478 AUGCCUGUCCUUUAGAGCU 7479 AGCUCUAAAGGACAGGCAU 7480 CUUCCUCUCUAGCUUAACC 7481 GGUUAAGCUAGAGAGGAAG 7482 UUCCUCUCUAGCUUAACCC 7483 GGGUUAAGCUAGAGAGGAA 7484 UCUCUAGCUUAACCCUGAU 7485 AUCAGGGUUAAGCUAGAGA 7486 UAGCUUAACCCUGAUCCUG 7487 CAGGAUCAGGGUUAAGCUA 7488 GACCAGGUGCAGGAGGAGU 7489 ACUCCUCCUGCACCUGGUC 7490 ACCAGGUGCAGGAGGAGUU 7491 AACUCCUCCUGCACCUGGU 7492 CCAGGUGCAGGAGGAGUUG 7493 CAACUCCUCCUGCACCUGG 7494 CAGGUGCAGGAGGAGUUGU 7495 ACAACUCCUCCUGCACCUG 7496 AGGUGCAGGAGGAGUUGUG 7497 CACAACUCCUCCUGCACCU 7498 UGCAGGAGGAGUUGUGGAA 7499 UUCCACAACUCCUCCUGCA 7500 GCAGGAGGAGUUGUGGAAU 7501 AUUCCACAACUCCUCCUGC 7502 AGGAGGAGUUGUGGAAUUG 7503 CAAUUCCACAACUCCUCCU 7504 GGAGGAGUUGUGGAAUUGU 7505 ACAAUUCCACAACUCCUCC 7506 GAGGAGUUGUGGAAUUGUC 7507 GACAAUUCCACAACUCCUC 7508 AGGAGUUGUGGAAUUGUCA 7509 UGACAAUUCCACAACUCCU 7510 GGAGUUGUGGAAUUGUCAA 7511 UUGACAAUUCCACAACUCC 7512 GAGUUGUGGAAUUGUCAAG 7513 CUUGACAAUUCCACAACUC 7514 AGUUGUGGAAUUGUCAAGG 7515 CCUUGACAAUUCCACAACU 7516 GUUGUGGAAUUGUCAAGGA 7517 UCCUUGACAAUUCCACAAC 7518 UGGAAUUGUCAAGGAUGUC 7519 GACAUCCUUGACAAUUCCA 7520 GGAAUUGUCAAGGAUGUCA 7521 UGACAUCCUUGACAAUUCC 7522 AGUCCAAGCGAGGGAGGGU 7523 ACCCUCCCUCGCUUGGACU 7524 CAAGCGAGGGAGGGUCUGA 7525 UCAGACCCUCCCUCGCUUG 7526 AAGCGAGGGAGGGUCUGAC 7527 GUCAGACCCUCCCUCGCUU 7528 CUGACCCAGUGCUGAUGGA 7529 UCCAUCAGCACUGGGUCAG 7530 AGAUUAGUGGUGGGUGUCU 7531 AGACACCCACCACUAAUCU 7532 AUUAGUGGUGGGUGUCUGG 7533 CCAGACACCCACCACUAAU 7534 UUAGUGGUGGGUGUCUGGU 7535 ACCAGACACCCACCACUAA 7536 UAGUGGUGGGUGUCUGGUA 7537 UACCAGACACCCACCACUA 7538 AGUGGUGGGUGUCUGGUAU 7539 AUACCAGACACCCACCACU 7540 GUGGUGGGUGUCUGGUAUG 7541 CAUACCAGACACCCACCAC 7542 UGGUGGGUGUCUGGUAUGA 7543 UCAUACCAGACACCCACCA 7544 GGUGGGUGUCUGGUAUGAG 7545 CUCAUACCAGACACCCACC 7546 GUGGGUGUCUGGUAUGAGG 7547 CCUCAUACCAGACACCCAC 7548 UGGGUGUCUGGUAUGAGGA 7549 UCCUCAUACCAGACACCCA 7550 GGGUGUCUGGUAUGAGGAU 7551 AUCCUCAUACCAGACACCC 7552 GGUGUCUGGUAUGAGGAUC 7553 GAUCCUCAUACCAGACACC 7554 GUGUCUGGUAUGAGGAUCU 7555 AGAUCCUCAUACCAGACAC 7556 UGUCUGGUAUGAGGAUCUA 7557 UAGAUCCUCAUACCAGACA 7558 CAAGGGUGUCCUACAGAGU 7559 ACUCUGUAGGACACCCUUG 7560 AAGGGUGUCCUACAGAGUG 7561 CACUCUGUAGGACACCCUU 7562 AGGGUGUCCUACAGAGUGG 7563 CCACUCUGUAGGACACCCU 7564 GGGUGUCCUACAGAGUGGA 7565 UCCACUCUGUAGGACACCC 7566 GGUGUCCUACAGAGUGGAG 7567 CUCCACUCUGUAGGACACC 7568 UCCUACAGAGUGGAGUGCU 7569 AGCACUCCACUCUGUAGGA 7570 AGUGGAGUGCUGUCAUAUG 7571 CAUAUGACAGCACUCCACU 7572 GUGGAGUGCUGUCAUAUGG 7573 CCAUAUGACAGCACUCCAC 7574 UGGAGUGCUGUCAUAUGGC 7575 GCCAUAUGACAGCACUCCA 7576 GGAGUGCUGUCAUAUGGCC 7577 GGCCAUAUGACAGCACUCC 7578 GAGUGCUGUCAUAUGGCCU 7579 AGGCCAUAUGACAGCACUC 7580 AGUGCUGUCAUAUGGCCUG 7581 CAGGCCAUAUGACAGCACU 7582 GUGCUGUCAUAUGGCCUGG 7583 CCAGGCCAUAUGACAGCAC 7584 UGCUGUCAUAUGGCCUGGG 7585 CCCAGGCCAUAUGACAGCA 7586 GCUGUCAUAUGGCCUGGGA 7587 UCCCAGGCCAUAUGACAGC 7588 CUGUCAUAUGGCCUGGGAC 7589 GUCCCAGGCCAUAUGACAG 7590 UGUCAUAUGGCCUGGGACG 7591 CGUCCCAGGCCAUAUGACA 7592 GUCAUAUGGCCUGGGACGG 7593 CCGUCCCAGGCCAUAUGAC 7594 AGAGGCCCAAGCACAGCAA 7595 UUGCUGUGCUUGGGCCUCU 7596 GAGGCCCAAGCACAGCAAG 7597 CUUGCUGUGCUUGGGCCUC 7598 AGGCCCAAGCACAGCAAGG 7599 CCUUGCUGUGCUUGGGCCU 7600 GGCCCAAGCACAGCAAGGA 7601 UCCUUGCUGUGCUUGGGCC 7602 CCAAGCACAGCAAGGACAU 7603 AUGUCCUUGCUGUGCUUGG 7604 GCCCGAUUCACCUUUGACG 7605 CGUCAAAGGUGAAUCGGGC 7606 GAUUCACCUUUGACGUGUA 7607 UACACGUCAAAGGUGAAUC 7608 AUUCACCUUUGACGUGUAC 7609 GUACACGUCAAAGGUGAAU 7610 UUGGCAGCCUGAAUGUCAA 7611 UUGACAUUCAGGCUGCCAA 7612 UGGCAGCCUGAAUGUCAAA 7613 UUUGACAUUCAGGCUGCCA 7614 GGCAGCCUGAAUGUCAAAG 7615 CUUUGACAUUCAGGCUGCC 7616 GCAGCCUGAAUGUCAAAGC 7617 GCUUUGACAUUCAGGCUGC 7618 CAGCCUGAAUGUCAAAGCC 7619 GGCUUUGACAUUCAGGCUG 7620 AGCCUGAAUGUCAAAGCCA 7621 UGGCUUUGACAUUCAGGCU 7622 GCCUGAAUGUCAAAGCCAC 7623 GUGGCUUUGACAUUCAGGC 7624 GUCAAAGCCACAUUCUACG 7625 CGUAGAAUGUGGCUUUGAC 7626 UCAAAGCCACAUUCUACGG 7627 CCGUAGAAUGUGGCUUUGA 7628 CAAAGCCACAUUCUACGGG 7629 CCCGUAGAAUGUGGCUUUG 7630 AAAGCCACAUUCUACGGGC 7631 GCCCGUAGAAUGUGGCUUU 7632 GCCACAUUCUACGGGCUCU 7633 AGAGCCCGUAGAAUGUGGC 7634 CCACAUUCUACGGGCUCUA 7635 UAGAGCCCGUAGAAUGUGG 7636 CACAUUCUACGGGCUCUAC 7637 GUAGAGCCCGUAGAAUGUG 7638 UUCUACGGGCUCUACUCUA 7639 UAGAGUAGAGCCCGUAGAA 7640 UCUACGGGCUCUACUCUAU 7641 AUAGAGUAGAGCCCGUAGA 7642 CUACGGGCUCUACUCUAUG 7643 CAUAGAGUAGAGCCCGUAG 7644 CUCUAUGAGUUGUGACUUU 7645 AAAGUCACAACUCAUAGAG 7646 UCUAUGAGUUGUGACUUUC 7647 GAAAGUCACAACUCAUAGA 7648 UGAGUUGUGACUUUCAAGG 7649 CCUUGAAAGUCACAACUCA 7650 GAGUUGUGACUUUCAAGGA 7651 UCCUUGAAAGUCACAACUC 7652 AGUUGUGACUUUCAAGGAC 7653 GUCCUUGAAAGUCACAACU 7654 GUUGUGACUUUCAAGGACU 7655 AGUCCUUGAAAGUCACAAC 7656 GACUUUCAAGGACUUGGCC 7657 GGCCAAGUCCUUGAAAGUC 7658 UUUCAAGGACUUGGCCCAA 7659 UUGGGCCAAGUCCUUGAAA 7660 UUCAAGGACUUGGCCCAAA 7661 UUUGGGCCAAGUCCUUGAA 7662 CCCUACAGUUGGAUAGUCC 7663 GGACUAUCCAACUGUAGGG 7664 CCUACAGUUGGAUAGUCCC 7665 GGGACUAUCCAACUGUAGG 7666 AUUCGUCCUCUUGCACCCA 7667 UGGGUGCAAGAGGACGAAU 7668 UUCGUCCUCUUGCACCCAC 7669 GUGGGUGCAAGAGGACGAA 7670 UCCUCUUGCACCCACCUAC 7671 GUAGGUGGGUGCAAGAGGA 7672 CCUCUUGCACCCACCUACC 7673 GGUAGGUGGGUGCAAGAGG 7674 CUCUUGCACCCACCUACCC 7675 GGGUAGGUGGGUGCAAGAG 7676 CUAGUUAGCUCUUGCUUGU 7677 ACAAGCAAGAGCUAACUAG 7678 UAGUUAGCUCUUGCUUGUG 7679 CACAAGCAAGAGCUAACUA 7680 AGUUAGCUCUUGCUUGUGG 7681 CCACAAGCAAGAGCUAACU 7682 UUAGCUCUUGCUUGUGGAA 7683 UUCCACAAGCAAGAGCUAA 7684 UCCUCAUCUCCCAGCUUGA 7685 UCAAGCUGGGAGAUGAGGA 7686 AUCUCCCAGCUUGAUGGCU 7687 AGCCAUCAAGCUGGGAGAU 7688 UCUCCCAGCUUGAUGGCUU 7689 AAGCCAUCAAGCUGGGAGA 7690 CUCCCAGCUUGAUGGCUUC 7691 GAAGCCAUCAAGCUGGGAG 7692 UCCCAGCUUGAUGGCUUCC 7693 GGAAGCCAUCAAGCUGGGA 7694 CCCAGCUUGAUGGCUUCCU 7695 AGGAAGCCAUCAAGCUGGG 7696 CCAGCUUGAUGGCUUCCUC 7697 GAGGAAGCCAUCAAGCUGG 7698 UGAUGGCUUCCUCCCAAGU 7699 ACUUGGGAGGAAGCCAUCA 7700 GAUGGCUUCCUCCCAAGUU 7701 AACUUGGGAGGAAGCCAUC 7702 GGCUUCCUCCCAAGUUUUC 7703 GAAAACUUGGGAGGAAGCC 7704 CCUCCCAAGUUUUCCAAAU 7705 AUUUGGAAAACUUGGGAGG 7706 CCCAAGUUUUCCAAAUCAU 7707 AUGAUUUGGAAAACUUGGG 7708 CCAAGUUUUCCAAAUCAUC 7709 GAUGAUUUGGAAAACUUGG 7710 CAAGUUUUCCAAAUCAUCU 7711 AGAUGAUUUGGAAAACUUG 7712 AAGUUUUCCAAAUCAUCUG 7713 CAGAUGAUUUGGAAAACUU 7714 GUUUUCCAAAUCAUCUGAU 7715 AUCAGAUGAUUUGGAAAAC 7716 AUCUGAUUUCCUCUUGUCU 7717 AGACAAGAGGAAAUCAGAU 7718 UCUGAUUUCCUCUUGUCUC 7719 GAGACAAGAGGAAAUCAGA 7720 CUGAUUUCCUCUUGUCUCU 7721 AGAGACAAGAGGAAAUCAG 7722 CUCUUGUCUCUGCCAUUCA 7723 UGAAUGGCAGAGACAAGAG 7724 GUUGGACCUCCACACUGCU 7725 AGCAGUGUGGAGGUCCAAC 7726 CCACACUGCUGCAAGGCCU 7727 AGGCCUUGCAGCAGUGUGG 7728 CACACUGCUGCAAGGCCUG 7729 CAGGCCUUGCAGCAGUGUG 7730 ACACUGCUGCAAGGCCUGG 7731 CCAGGCCUUGCAGCAGUGU 7732 UGCAAGGCCUGGGCCAUAU 7733 AUAUGGCCCAGGCCUUGCA 7734 GCAAGGCCUGGGCCAUAUG 7735 CAUAUGGCCCAGGCCUUGC 7736 CAAGGCCUGGGCCAUAUGU 7737 ACAUAUGGCCCAGGCCUUG 7738 AAGGCCUGGGCCAUAUGUU 7739 AACAUAUGGCCCAGGCCUU 7740 AGGCCUGGGCCAUAUGUUG 7741 CAACAUAUGGCCCAGGCCU 7742 GGCCUGGGCCAUAUGUUGC 7743 GCAACAUAUGGCCCAGGCC 7744 GCCUGGGCCAUAUGUUGCU 7745 AGCAACAUAUGGCCCAGGC 7746 CCUGGGCCAUAUGUUGCUG 7747 CAGCAACAUAUGGCCCAGG 7748 GGCCAUAUGUUGCUGGGAA 7749 UUCCCAGCAACAUAUGGCC 7750 CCAUAUGUUGCUGGGAAUU 7751 AAUUCCCAGCAACAUAUGG 7752 GGAAUUUCCUCCACCCUUC 7753 GAAGGGUGGAGGAAAUUCC 7754 GAAUUUCCUCCACCCUUCG 7755 CGAAGGGUGGAGGAAAUUC 7756 AAUUUCCUCCACCCUUCGU 7757 ACGAAGGGUGGAGGAAAUU 7758 AUUUCCUCCACCCUUCGUC 7759 GACGAAGGGUGGAGGAAAU 7760 UUUCCUCCACCCUUCGUCA 7761 UGACGAAGGGUGGAGGAAA 7762 UUCCUCCACCCUUCGUCAU 7763 AUGACGAAGGGUGGAGGAA 7764 UCCUCCACCCUUCGUCAUG 7765 CAUGACGAAGGGUGGAGGA 7766 CCUCCACCCUUCGUCAUGC 7767 GCAUGACGAAGGGUGGAGG 7768 CUCCACCCUUCGUCAUGCA 7769 UGCAUGACGAAGGGUGGAG 7770 CCUUCGUCAUGCAGUGGAG 7771 CUCCACUGCAUGACGAAGG 7772 CUUCGUCAUGCAGUGGAGG 7773 CCUCCACUGCAUGACGAAG 7774 UUCGUCAUGCAGUGGAGGG 7775 CCCUCCACUGCAUGACGAA 7776 CGCCUCCAUUCCUACUAAG 7777 CUUAGUAGGAAUGGAGGCG 7778 GCCUCCAUUCCUACUAAGG 7779 CCUUAGUAGGAAUGGAGGC 7780 CCUCCAUUCCUACUAAGGG 7781 CCCUUAGUAGGAAUGGAGG 7782 CAGAAUCAUUCCAACCGAC 7783 GUCGGUUGGAAUGAUUCUG 7784 AGAAUCAUUCCAACCGACC 7785 GGUCGGUUGGAAUGAUUCU 7786 GAAUCAUUCCAACCGACCC 7787 GGGUCGGUUGGAAUGAUUC 7788 AAUCAUUCCAACCGACCCA 7789 UGGGUCGGUUGGAAUGAUU 7790 AUCAUUCCAACCGACCCAC 7791 GUGGGUCGGUUGGAAUGAU 7792 UCAUUCCAACCGACCCACU 7793 AGUGGGUCGGUUGGAAUGA 7794 UCCAACCGACCCACUGCAA 7795 UUGCAGUGGGUCGGUUGGA 7796 CCAACCGACCCACUGCAAA 7797 UUUGCAGUGGGUCGGUUGG 7798 CAACCGACCCACUGCAAAG 7799 CUUUGCAGUGGGUCGGUUG 7800 AACCGACCCACUGCAAAGA 7801 UCUUUGCAGUGGGUCGGUU 7802 ACCGACCCACUGCAAAGAC 7803 GUCUUUGCAGUGGGUCGGU 7804 CCGACCCACUGCAAAGACU 7805 AGUCUUUGCAGUGGGUCGG 7806 CGACCCACUGCAAAGACUA 7807 UAGUCUUUGCAGUGGGUCG 7808 GACCCACUGCAAAGACUAU 7809 AUAGUCUUUGCAGUGGGUC 7810 ACCCACUGCAAAGACUAUG 7811 CAUAGUCUUUGCAGUGGGU 7812 ACUGCAAAGACUAUGACAG 7813 CUGUCAUAGUCUUUGCAGU 7814 CUGCAAAGACUAUGACAGC 7815 GCUGUCAUAGUCUUUGCAG 7816 UGCAAAGACUAUGACAGCA 7817 UGCUGUCAUAGUCUUUGCA 7818 GCAAAGACUAUGACAGCAU 7819 AUGCUGUCAUAGUCUUUGC 7820 AAAGACUAUGACAGCAUCA 7821 UGAUGCUGUCAUAGUCUUU 7822 AAGACUAUGACAGCAUCAA 7823 UUGAUGCUGUCAUAGUCUU 7824 AGACUAUGACAGCAUCAAA 7825 UUUGAUGCUGUCAUAGUCU 7826 GACUAUGACAGCAUCAAAU 7827 AUUUGAUGCUGUCAUAGUC 7828 CUAUGACAGCAUCAAAUUU 7829 AAAUUUGAUGCUGUCAUAG 7830 UAUGACAGCAUCAAAUUUC 7831 GAAAUUUGAUGCUGUCAUA 7832 GCAUCAAAUUUCAGGACCU 7833 AGGUCCUGAAAUUUGAUGC 7834 AUCAAAUUUCAGGACCUGC 7835 GCAGGUCCUGAAAUUUGAU 7836 UCAAAUUUCAGGACCUGCA 7837 UGCAGGUCCUGAAAUUUGA 7838 UUCAGGACCUGCAGACAGU 7839 ACUGUCUGCAGGUCCUGAA 7840 UCAGGACCUGCAGACAGUA 7841 UACUGUCUGCAGGUCCUGA 7842 CAGGACCUGCAGACAGUAC 7843 GUACUGUCUGCAGGUCCUG 7844 AGGACCUGCAGACAGUACA 7845 UGUACUGUCUGCAGGUCCU 7846 GGACCUGCAGACAGUACAG 7847 CUGUACUGUCUGCAGGUCC 7848 CUGCAGACAGUACAGGCUA 7849 UAGCCUGUACUGUCUGCAG 7850 GACAGUACAGGCUAGAUAA 7851 UUAUCUAGCCUGUACUGUC 7852 ACAGUACAGGCUAGAUAAC 7853 GUUAUCUAGCCUGUACUGU 7854 CAGUACAGGCUAGAUAACC 7855 GGUUAUCUAGCCUGUACUG 7856 AGUACAGGCUAGAUAACCC 7857 GGGUUAUCUAGCCUGUACU 7858 GUACAGGCUAGAUAACCCA 7859 UGGGUUAUCUAGCCUGUAC 7860 UACAGGCUAGAUAACCCAC 7861 GUGGGUUAUCUAGCCUGUA 7862 GCUAGAUAACCCACCCAAU 7863 AUUGGGUGGGUUAUCUAGC 7864 CUAGAUAACCCACCCAAUU 7865 AAUUGGGUGGGUUAUCUAG 7866 AGAUAACCCACCCAAUUUC 7867 GAAAUUGGGUGGGUUAUCU 7868 GAUAACCCACCCAAUUUCC 7869 GGAAAUUGGGUGGGUUAUC 7870 AACCUUUCAGCAUAACGCC 7871 GGCGUUAUGCUGAAAGGUU 7872 ACCUUUCAGCAUAACGCCU 7873 AGGCGUUAUGCUGAAAGGU 7874 CCUUUCAGCAUAACGCCUC 7875 GAGGCGUUAUGCUGAAAGG 7876 CUUUCAGCAUAACGCCUCA 7877 UGAGGCGUUAUGCUGAAAG 7878 UUUCAGCAUAACGCCUCAC 7879 GUGAGGCGUUAUGCUGAAA 7880 UUCAGCAUAACGCCUCACA 7881 UGUGAGGCGUUAUGCUGAA 7882 UCAGCAUAACGCCUCACAU 7883 AUGUGAGGCGUUAUGCUGA 7884 CAGCAUAACGCCUCACAUC 7885 GAUGUGAGGCGUUAUGCUG 7886 AGCAUAACGCCUCACAUCC 7887 GGAUGUGAGGCGUUAUGCU 7888 GCAUAACGCCUCACAUCCC 7889 GGGAUGUGAGGCGUUAUGC 7890 AACGCCUCACAUCCCAAGU 7891 ACUUGGGAUGUGAGGCGUU 7892 ACGCCUCACAUCCCAAGUC 7893 GACUUGGGAUGUGAGGCGU 7894 CGCCUCACAUCCCAAGUCU 7895 AGACUUGGGAUGUGAGGCG 7896 UCACAUCCCAAGUCUAUAC 7897 GUAUAGACUUGGGAUGUGA 7898 CACAUCCCAAGUCUAUACC 7899 GGUAUAGACUUGGGAUGUG 7900 ACAUCCCAAGUCUAUACCC 7901 GGGUAUAGACUUGGGAUGU 7902 CAUCCCAAGUCUAUACCCU 7903 AGGGUAUAGACUUGGGAUG 7904 AAUGCUGUUCUUUCCUAGC 7905 GCUAGGAAAGAACAGCAUU 7906 AUGCUGUUCUUUCCUAGCC 7907 GGCUAGGAAAGAACAGCAU 7908 CUGUUCUUUCCUAGCCACC 7909 GGUGGCUAGGAAAGAACAG 7910 UGUUCUUUCCUAGCCACCU 7911 AGGUGGCUAGGAAAGAACA 7912 GCCAAGAUCAAGAUGUCCC 7913 GGGACAUCUUGAUCUUGGC 7914 UCUUGAUCCCAGCCUGACU 7915 AGUCAGGCUGGGAUCAAGA 7916 CUUGAUCCCAGCCUGACUG 7917 CAGUCAGGCUGGGAUCAAG 7918 UUGAUCCCAGCCUGACUGC 7919 GCAGUCAGGCUGGGAUCAA 7920 UGAUCCCAGCCUGACUGCU 7921 AGCAGUCAGGCUGGGAUCA 7922 CUGACUGCUGCUACAUCUA 7923 UAGAUGUAGCAGCAGUCAG 7924 GACUGCUGCUACAUCUAAU 7925 AUUAGAUGUAGCAGCAGUC 7926 ACUGCUGCUACAUCUAAUC 7927 GAUUAGAUGUAGCAGCAGU 7928 CUGCUGCUACAUCUAAUCC 7929 GGAUUAGAUGUAGCAGCAG 7930 UGCUGCUACAUCUAAUCCC 7931 GGGAUUAGAUGUAGCAGCA 7932 CCUACCAAUGCCUCCUGUC 7933 GACAGGAGGCAUUGGUAGG 7934 CUACCAAUGCCUCCUGUCC 7935 GGACAGGAGGCAUUGGUAG 7936 CCAAUGCCUCCUGUCCCUA 7937 UAGGGACAGGAGGCAUUGG 7938 CAAUGCCUCCUGUCCCUAA 7939 UUAGGGACAGGAGGCAUUG 7940 AAUGCCUCCUGUCCCUAAA 7941 UUUAGGGACAGGAGGCAUU 7942 CCCAGCAUACUGAUGACAG 7943 CUGUCAUCAGUAUGCUGGG 7944 CCAGCAUACUGAUGACAGC 7945 GCUGUCAUCAGUAUGCUGG 7946 CAUACUGAUGACAGCCCUC 7947 GAGGGCUGUCAUCAGUAUG 7948 AUACUGAUGACAGCCCUCU 7949 AGAGGGCUGUCAUCAGUAU 7950 UACUGAUGACAGCCCUCUC 7951 GAGAGGGCUGUCAUCAGUA 7952 ACUGAUGACAGCCCUCUCU 7953 AGAGAGGGCUGUCAUCAGU 7954 CUGAUGACAGCCCUCUCUG 7955 CAGAGAGGGCUGUCAUCAG 7956 UGAUGACAGCCCUCUCUGA 7957 UCAGAGAGGGCUGUCAUCA 7958 GAUGACAGCCCUCUCUGAC 7959 GUCAGAGAGGGCUGUCAUC 7960 AUGACAGCCCUCUCUGACU 7961 AGUCAGAGAGGGCUGUCAU 7962 UGACAGCCCUCUCUGACUU 7963 AAGUCAGAGAGGGCUGUCA 7964 GACAGCCCUCUCUGACUUU 7965 AAAGUCAGAGAGGGCUGUC 7966 ACAGCCCUCUCUGACUUUA 7967 UAAAGUCAGAGAGGGCUGU 7968 CAGCCCUCUCUGACUUUAC 7969 GUAAAGUCAGAGAGGGCUG 7970 AGCCCUCUCUGACUUUACC 7971 GGUAAAGUCAGAGAGGGCU 7972 GCCCUCUCUGACUUUACCU 7973 AGGUAAAGUCAGAGAGGGC 7974 CCCUCUCUGACUUUACCUU 7975 AAGGUAAAGUCAGAGAGGG 7976 CCUCUCUGACUUUACCUUG 7977 CAAGGUAAAGUCAGAGAGG 7978 CUCUCUGACUUUACCUUGA 7979 UCAAGGUAAAGUCAGAGAG 7980 AGAUCUGUCUUCAUACCCU 7981 AGGGUAUGAAGACAGAUCU 7982 GAUCUGUCUUCAUACCCUU 7983 AAGGGUAUGAAGACAGAUC 7984 CUGUCUUCAUACCCUUCCC 7985 GGGAAGGGUAUGAAGACAG 7986

In some embodiments, the siRNA molecules targeted to Transcript C comprise or consist of the nucleotide sequences (sense and antisense strands) shown in Table 10.

TABLE 10 SEQ SEQ ID ID Sense Sequence NO: Antisense Sequence NO: ACACCAGAAGUCACAUUUC 7987 GAAAUGUGACUUCUGGUGU 7988 GAAGUCACAUUUCAUCCUU 7989 AAGGAUGAAAUGUGACUUC 7990 AAGUCACAUUUCAUCCUUU 7991 AAAGGAUGAAAUGUGACUU 7992 AGUCACAUUUCAUCCUUUU 7993 AAAAGGAUGAAAUGUGACU 7994 UUUCAUCCUUUUACAUGGU 7995 ACCAUGUAAAAGGAUGAAA 7996 UUCAUCCUUUUACAUGGUU 7997 AACCAUGUAAAAGGAUGAA 7998 UCAUCCUUUUACAUGGUUC 7999 GAACCAUGUAAAAGGAUGA 8000 CAUCCUUUUACAUGGUUCC 8001 GGAACCAUGUAAAAGGAUG 8002 UGGUUCCCAUCUACCCUCA 8003 UGAGGGUAGAUGGGAACCA 8004 GGUUCCCAUCUACCCUCAC 8005 GUGAGGGUAGAUGGGAACC 8006 GUUCCCAUCUACCCUCACA 8007 UGUGAGGGUAGAUGGGAAC 8008 GGCAAUUCUUCCUCCAGGA 8009 UCCUGGAGGAAGAAUUGCC 8010 GCAAUUCUUCCUCCAGGAC 8011 GUCCUGGAGGAAGAAUUGC 8012 CAAUUCUUCCUCCAGGACC 8013 GGUCCUGGAGGAAGAAUUG 8014 AAUUCUUCCUCCAGGACCC 8015 GGGUCCUGGAGGAAGAAUU 8016 CCCUUGGACUUUGCCCUUC 8017 GAAGGGCAAAGUCCAAGGG 8018 CCUUGGACUUUGCCCUUCU 8019 AGAAGGGCAAAGUCCAAGG 8020 CUUGGACUUUGCCCUUCUU 8021 AAGAAGGGCAAAGUCCAAG 8022 UUGGACUUUGCCCUUCUUA 8023 UAAGAAGGGCAAAGUCCAA 8024 UGGACUUUGCCCUUCUUAC 8025 GUAAGAAGGGCAAAGUCCA 8026 GGACUUUGCCCUUCUUACU 8027 AGUAAGAAGGGCAAAGUCC 8028 UUUGCCCUUCUUACUGGCC 8029 GGCCAGUAAGAAGGGCAAA 8030 UUGCCCUUCUUACUGGCCA 8031 UGGCCAGUAAGAAGGGCAA 8032 UGCCCUUCUUACUGGCCAG 8033 CUGGCCAGUAAGAAGGGCA 8034 UCUUACUGGCCAGGCAGGG 8035 CCCUGCCUGGCCAGUAAGA 8036 GGCCAGAGUCCAGGCUUGA 8037 UCAAGCCUGGACUCUGGCC 8038 GCCAGAGUCCAGGCUUGAC 8039 GUCAAGCCUGGACUCUGGC 8040 GUCCAGGCUUGACUCAUUC 8041 GAAUGAGUCAAGCCUGGAC 8042 AGGCUUGACUCAUUCCCAC 8043 GUGGGAAUGAGUCAAGCCU 8044 GACUCAUUCCCACCUUGUC 8045 GACAAGGUGGGAAUGAGUC 8046 ACUCAUUCCCACCUUGUCC 8047 GGACAAGGUGGGAAUGAGU 8048 UCAUUCCCACCUUGUCCUG 8049 CAGGACAAGGUGGGAAUGA 8050 CACCUUGUCCUGGGCUGAG 8051 CUCAGCCCAGGACAAGGUG 8052 ACCACCCAGCCCAGAAGUU 8053 AACUUCUGGGCUGGGUGGU 8054 CCACCCAGCCCAGAAGUUC 8055 GAACUUCUGGGCUGGGUGG 8056 CACCCAGCCCAGAAGUUCC 8057 GGAACUUCUGGGCUGGGUG 8058 ACCCAGCCCAGAAGUUCCA 8059 UGGAACUUCUGGGCUGGGU 8060 CCAGAAGUUCCAGGGAAGG 8061 CCUUCCCUGGAACUUCUGG 8062 CAGAAGUUCCAGGGAAGGA 8063 UCCUUCCCUGGAACUUCUG 8064 AACUCUCCGGUCCACCAUG 8065 CAUGGUGGACCGGAGAGUU 8066 ACUCUCCGGUCCACCAUGG 8067 CCAUGGUGGACCGGAGAGU 8068 CACCAUGGAGUACCUCUCA 8069 UGAGAGGUACUCCAUGGUG 8070 ACCAUGGAGUACCUCUCAG 8071 CUGAGAGGUACUCCAUGGU 8072 UGGAGUACCUCUCAGCUCU 8073 AGAGCUGAGAGGUACUCCA 8074 GGAGUACCUCUCAGCUCUG 8075 CAGAGCUGAGAGGUACUCC 8076 GAGUACCUCUCAGCUCUGA 8077 UCAGAGCUGAGAGGUACUC 8078 AGUACCUCUCAGCUCUGAA 8079 UUCAGAGCUGAGAGGUACU 8080 CCAGUGACUUACUCAGGUG 8081 CACCUGAGUAAGUCACUGG 8082 CAGUGACUUACUCAGGUGA 8083 UCACCUGAGUAAGUCACUG 8084 AGUGACUUACUCAGGUGAC 8085 GUCACCUGAGUAAGUCACU 8086 GUGACUUACUCAGGUGACU 8087 AGUCACCUGAGUAAGUCAC 8088 UGACUUACUCAGGUGACUG 8089 CAGUCACCUGAGUAAGUCA 8090 GACUUACUCAGGUGACUGC 8091 GCAGUCACCUGAGUAAGUC 8092 ACUUACUCAGGUGACUGCU 8093 AGCAGUCACCUGAGUAAGU 8094 CUUACUCAGGUGACUGCUA 8095 UAGCAGUCACCUGAGUAAG 8096 UUACUCAGGUGACUGCUAA 8097 UUAGCAGUCACCUGAGUAA 8098 UACUCAGGUGACUGCUAAC 8099 GUUAGCAGUCACCUGAGUA 8100 ACUCAGGUGACUGCUAACC 8101 GGUUAGCAGUCACCUGAGU 8102 CUCAGGUGACUGCUAACCC 8103 GGGUUAGCAGUCACCUGAG 8104 GGUGACUGCUAACCCUCCG 8105 CGGAGGGUUAGCAGUCACC 8106 GUGACUGCUAACCCUCCGC 8107 GCGGAGGGUUAGCAGUCAC 8108 UGACUGCUAACCCUCCGCU 8109 AGCGGAGGGUUAGCAGUCA 8110 GACUGCUAACCCUCCGCUC 8111 GAGCGGAGGGUUAGCAGUC 8112 ACUGCUAACCCUCCGCUCU 8113 AGAGCGGAGGGUUAGCAGU 8114 CUGCUAACCCUCCGCUCUA 8115 UAGAGCGGAGGGUUAGCAG 8116 UGCUAACCCUCCGCUCUAC 8117 GUAGAGCGGAGGGUUAGCA 8118 AACCCUCCGCUCUACCCUC 8119 GAGGGUAGAGCGGAGGGUU 8120 ACUCCACAGUGGGCUUGUC 8121 GACAAGCCCACUGUGGAGU 8122 CUCCACAGUGGGCUUGUCA 8123 UGACAAGCCCACUGUGGAG 8124 UCCACAGUGGGCUUGUCAA 8125 UUGACAAGCCCACUGUGGA 8126 CCACAGUGGGCUUGUCAAG 8127 CUUGACAAGCCCACUGUGG 8128 GUCAAGCUCCUGAGCCACC 8129 GGUGGCUCAGGAGCUUGAC 8130 CCAUGGUCUCUCCCUCAUC 8131 GAUGAGGGAGAGACCAUGG 8132 CAUGGUCUCUCCCUCAUCC 8133 GGAUGAGGGAGAGACCAUG 8134 AUGGUCUCUCCCUCAUCCC 8135 GGGAUGAGGGAGAGACCAU 8136 UCUCUCCCUCAUCCCUAAU 8137 UCGAUUAGGGAUGAGGGAG 8144 CUCUCCCUCAUCCCUAAUC 8139 GAUUAGGGAUGAGGGAGAG 8140 UCUCCCUCAUCCCUAAUCG 8141 CGAUUAGGGAUGAGGGAGA 8142 CUCCCUCAUCCCUAAUCGA 8143 UCGAUUAGGGAUGAGGGAG 8144 UCCCUCAUCCCUAAUCGAU 8145 AUCGAUUAGGGAUGAGGGA 8146 CCCUCAUCCCUAAUCGAUA 8147 UAUCGAUUAGGGAUGAGGG 8148 CCUCAUCCCUAAUCGAUAA 8149 UUAUCGAUUAGGGAUGAGG 8150 CUCAUCCCUAAUCGAUAAA 8151 UUUAUCGAUUAGGGAUGAG 8152 AACCUAGAUCUCUCCCUCC 8153 GGAGGGAGAGAUCUAGGUU 8154 ACCUAGAUCUCUCCCUCCC 8155 GGGAGGGAGAGAUCUAGGU 8156 CUAGAUCUCUCCCUCCCUA 8157 UAGGGAGGGAGAGAUCUAG 8158 UAGAUCUCUCCCUCCCUAG 8159 CUAGGGAGGGAGAGAUCUA 8160 AGAUCUCUCCCUCCCUAGC 8161 GCUAGGGAGGGAGAGAUCU 8162 GAUCUCUCCCUCCCUAGCC 8163 GGCUAGGGAGGGAGAGAUC 8164 AUCUCUCCCUCCCUAGCCC 8165 GGGCUAGGGAGGGAGAGAU 8166 UAGCCCUCUAGCCACUCUA 8167 UAGAGUGGCUAGAGGGCUA 8168 AGCCCUCUAGCCACUCUAC 8169 GUAGAGUGGCUAGAGGGCU 8170 CUCUAGCCACUCUACCCUC 8171 GAGGGUAGAGUGGCUAGAG 8172 UCUAGCCACUCUACCCUCA 8173 UGAGGGUAGAGUGGCUAGA 8174 CUAGCCACUCUACCCUCAU 8175 AUGAGGGUAGAGUGGCUAG 8176 UAGCCACUCUACCCUCAUC 8177 GAUGAGGGUAGAGUGGCUA 8178 AGCCACUCUACCCUCAUCA 8179 UGAUGAGGGUAGAGUGGCU 8180 GCCACUCUACCCUCAUCAU 8181 AUGAUGAGGGUAGAGUGGC 8182 CCACUCUACCCUCAUCAUG 8183 CAUGAUGAGGGUAGAGUGG 8184 CACUCUACCCUCAUCAUGC 8185 GCAUGAUGAGGGUAGAGUG 8186 ACUCUACCCUCAUCAUGCC 8187 GGCAUGAUGAGGGUAGAGU 8188 CUCUACCCUCAUCAUGCCC 8189 GGGCAUGAUGAGGGUAGAG 8190 UCUACCCUCAUCAUGCCCU 8191 AGGGCAUGAUGAGGGUAGA 8192 CUACCCUCAUCAUGCCCUU 8193 AAGGGCAUGAUGAGGGUAG 8194 UACCCUCAUCAUGCCCUUU 8195 AAAGGGCAUGAUGAGGGUA 8196 ACCCUCAUCAUGCCCUUUA 8197 UAAAGGGCAUGAUGAGGGU 8198 CCCUCAUCAUGCCCUUUAC 8199 GUAAAGGGCAUGAUGAGGG 8200 CUCAUCAUGCCCUUUACAC 8201 GUGUAAAGGGCAUGAUGAG 8202 UCAUCAUGCCCUUUACACU 8203 AGUGUAAAGGGCAUGAUGA 8204 CCCUUCUUGACUUUUCUUC 8205 GAAGAAAAGUCAAGAAGGG 8206 CUUCUUGACUUUUCUUCUC 8207 GAGAAGAAAAGUCAAGAAG 8208 GACUUUUCUUCUCAACUAC 8209 GUAGUUGAGAAGAAAAGUC 8210 ACUUUUCUUCUCAACUACC 8211 GGUAGUUGAGAAGAAAAGU 8212 CUUUUCUUCUCAACUACCA 8213 UGGUAGUUGAGAAGAAAAG 8214 UUUUCUUCUCAACUACCAG 8215 CUGGUAGUUGAGAAGAAAA 8216 UAUCUAAUAUAAGCUCGGA 8217 UCCGAGCUUAUAUUAGAUA 8218 AUCUAAUAUAAGCUCGGAG 8219 CUCCGAGCUUAUAUUAGAU 8220 UCUAAUAUAAGCUCGGAGU 8221 ACUCCGAGCUUAUAUUAGA 8222 CUAAUAUAAGCUCGGAGUU 8223 AACUCCGAGCUUAUAUUAG 8224 UAAUAUAAGCUCGGAGUUU 8225 AAACUCCGAGCUUAUAUUA 8226 AAUAUAAGCUCGGAGUUUG 8227 CAAACUCCGAGCUUAUAUU 8228 AUAUAAGCUCGGAGUUUGG 8229 CCAAACUCCGAGCUUAUAU 8230 UAUAAGCUCGGAGUUUGGA 8231 UCCAAACUCCGAGCUUAUA 8232 AUAAGCUCGGAGUUUGGAC 8233 GUCCAAACUCCGAGCUUAU 8234 UAAGCUCGGAGUUUGGACG 8235 CGUCCAAACUCCGAGCUUA 8236 AAGCUCGGAGUUUGGACGG 8237 CCGUCCAAACUCCGAGCUU 8238 AGCUCGGAGUUUGGACGGA 8239 UCCGUCCAAACUCCGAGCU 8240 GCUCGGAGUUUGGACGGAG 8241 CUCCGUCCAAACUCCGAGC 8242 CUCGGAGUUUGGACGGAGG 8243 CCUCCGUCCAAACUCCGAG 8244 UCGGAGUUUGGACGGAGGG 8245 CCCUCCGUCCAAACUCCGA 8246 CGGAGUUUGGACGGAGGGU 8247 ACCCUCCGUCCAAACUCCG 8248 UUUGGACGGAGGGUCUGGA 8249 UCCAGACCCUCCGUCCAAA 8250 CCCAGCGACCUUUCCGUGU 8251 ACACGGAAAGGUCGCUGGG 8252 CCAGCGACCUUUCCGUGUC 8253 GACACGGAAAGGUCGCUGG 8254 CAGCGACCUUUCCGUGUCU 8255 AGACACGGAAAGGUCGCUG 8256 AGCGACCUUUCCGUGUCUG 8257 CAGACACGGAAAGGUCGCU 8258 GCGACCUUUCCGUGUCUGU 8259 ACAGACACGGAAAGGUCGC 8260 CGACCUUUCCGUGUCUGUG 8261 CACAGACACGGAAAGGUCG 8262 CUUUCCGUGUCUGUGAUCA 8263 UGAUCACAGACACGGAAAG 8264 UUUCCGUGUCUGUGAUCAC 8265 GUGAUCACAGACACGGAAA 8266 UUCCGUGUCUGUGAUCACA 8267 UGUGAUCACAGACACGGAA 8268 AAGGCCUGACAGCUGCCAC 8269 GUGGCAGCUGUCAGGCCUU 8270 GCCAGGAGCUGCUAGCCAA 8271 UUGGCUAGCAGCUCCUGGC 8272 CCAGGAGCUGCUAGCCAAA 8273 UUUGGCUAGCAGCUCCUGG 8274 GAGCUGCUAGCCAAAGUAA 8275 UUACUUUGGCUAGCAGCUC 8276 AGCUGCUAGCCAAAGUAAG 8277 CUUACUUUGGCUAGCAGCU 8278 GCUGCUAGCCAAAGUAAGU 8279 ACUUACUUUGGCUAGCAGC 8280 CUGCUAGCCAAAGUAAGUA 8281 UACUUACUUUGGCUAGCAG 8282 UGCUAGCCAAAGUAAGUAG 8283 CUACUUACUUUGGCUAGCA 8284 GCUAGCCAAAGUAAGUAGG 8285 CCUACUUACUUUGGCUAGC 8286 UAGCCAAAGUAAGUAGGCC 8287 GGCCUACUUACUUUGGCUA 8288 AGCCAAAGUAAGUAGGCCA 8289 UGGCCUACUUACUUUGGCU 8290 GCCAAAGUAAGUAGGCCAA 8291 UUGGCCUACUUACUUUGGC 8292 CCAAAGUAAGUAGGCCAAG 8293 CUUGGCCUACUUACUUUGG 8294 CAAAGUAAGUAGGCCAAGU 8295 ACUUGGCCUACUUACUUUG 8296 AAAGUAAGUAGGCCAAGUU 8297 AACUUGGCCUACUUACUUU 8298 AAGUAAGUAGGCCAAGUUC 8299 GAACUUGGCCUACUUACUU 8300 AGUAAGUAGGCCAAGUUCC 8301 GGAACUUGGCCUACUUACU 8302 GUAAGUAGGCCAAGUUCCU 8303 AGGAACUUGGCCUACUUAC 8304 UAAGUAGGCCAAGUUCCUC 8305 GAGGAACUUGGCCUACUUA 8306 UAGGCCAAGUUCCUCGGUU 8307 AACCGAGGAACUUGGCCUA 8308 AGGCCAAGUUCCUCGGUUC 8309 GAACCGAGGAACUUGGCCU 8310 GGCCAAGUUCCUCGGUUCC 8311 GGAACCGAGGAACUUGGCC 8312 GCCAAGUUCCUCGGUUCCU 8313 AGGAACCGAGGAACUUGGC 8314 CCAAGUUCCUCGGUUCCUA 8315 UAGGAACCGAGGAACUUGG 8316 CAAGUUCCUCGGUUCCUAU 8317 AUAGGAACCGAGGAACUUG 8318 AAGUUCCUCGGUUCCUAUA 8319 UAUAGGAACCGAGGAACUU 8320 AGUUCCUCGGUUCCUAUAG 8321 CUAUAGGAACCGAGGAACU 8322 GUUCCUCGGUUCCUAUAGC 8323 GCUAUAGGAACCGAGGAAC 8324 UUCCUCGGUUCCUAUAGCA 8325 UGCUAUAGGAACCGAGGAA 8326 UCCUCGGUUCCUAUAGCAG 8327 CUGCUAUAGGAACCGAGGA 8328 CAGUGGCAACUUGUGAUGA 8329 UCAUCACAAGUUGCCACUG 8330 AGUGGCAACUUGUGAUGAU 8331 AUCAUCACAAGUUGCCACU 8332 GUGGCAACUUGUGAUGAUG 8333 CAUCAUCACAAGUUGCCAC 8334 GGCAACUUGUGAUGAUGGA 8335 UCCAUCAUCACAAGUUGCC 8336 ACUUGUGAUGAUGGAGCAG 8337 CUGCUCCAUCAUCACAAGU 8338 CUUGUGAUGAUGGAGCAGA 8339 UCUGCUCCAUCAUCACAAG 8340 GUGAUGAUGGAGCAGAGGG 8341 CCCUCUGCUCCAUCAUCAC 8342 UGAUGAUGGAGCAGAGGGC 8343 GCCCUCUGCUCCAUCAUCA 8344 UGGAGCAGAGGGCUGAAGU 8345 ACUUCAGCCCUCUGCUCCA 8346 GGAGCAGAGGGCUGAAGUC 8347 GACUUCAGCCCUCUGCUCC 8348 GAGCAGAGGGCUGAAGUCA 8349 UGACUUCAGCCCUCUGCUC 8350 CUAAAAGCAGCGGAGUGGG 8351 CCCACUCCGCUGCUUUUAG 8352 UAAAAGCAGCGGAGUGGGC 8353 GCCCACUCCGCUGCUUUUA 8354 AAAAGCAGCGGAGUGGGCC 8355 GGCCCACUCCGCUGCUUUU 8356 AAAGCAGCGGAGUGGGCCU 8357 AGGCCCACUCCGCUGCUUU 8358 AAGCAGCGGAGUGGGCCUA 8359 UAGGCCCACUCCGCUGCUU 8360 AGCAGCGGAGUGGGCCUAA 8361 UUAGGCCCACUCCGCUGCU 8362 GCAGCGGAGUGGGCCUAAU 8363 AUUAGGCCCACUCCGCUGC 8364 CAGCGGAGUGGGCCUAAUG 8365 CAUUAGGCCCACUCCGCUG 8366 AGCGGAGUGGGCCUAAUGA 8367 UCAUUAGGCCCACUCCGCU 8368 GCGGAGUGGGCCUAAUGAG 8369 CUCAUUAGGCCCACUCCGC 8370 AGUGGGCCUAAUGAGCUCU 8371 AGAGCUCAUUAGGCCCACU 8372 GUGGGCCUAAUGAGCUCUG 8373 CAGAGCUCAUUAGGCCCAC 8374 UGGGCCUAAUGAGCUCUGG 8375 CCAGAGCUCAUUAGGCCCA 8376 GGGCCUAAUGAGCUCUGGU 8377 ACCAGAGCUCAUUAGGCCC 8378 GGCCUAAUGAGCUCUGGUC 8379 GACCAGAGCUCAUUAGGCC 8380 GCCUAAUGAGCUCUGGUCA 8381 UGACCAGAGCUCAUUAGGC 8382 CCUAAUGAGCUCUGGUCAA 8383 UUGACCAGAGCUCAUUAGG 8384 CUAAUGAGCUCUGGUCAAU 8385 AUUGACCAGAGCUCAUUAG 8386 UAAUGAGCUCUGGUCAAUU 8387 AAUUGACCAGAGCUCAUUA 8388 AAUGAGCUCUGGUCAAUUU 8389 AAAUUGACCAGAGCUCAUU 8390 AUGAGCUCUGGUCAAUUUG 8391 CAAAUUGACCAGAGCUCAU 8392 UGAGCUCUGGUCAAUUUGU 8393 ACAAAUUGACCAGAGCUCA 8394 CUGGUCAAUUUGUUCAUUU 8395 AAAUGAACAAAUUGACCAG 8396 CAAUUUGUUCAUUUUCCAC 8397 GUGGAAAAUGAACAAAUUG 8398 AGUGAGCUUUUCUAUGGGA 8399 UCCCAUAGAAAAGCUCACU 8400 AGCUUUUCUAUGGGAGCAG 8401 CUGCUCCCAUAGAAAAGCU 8402 GAAUUCAGAAGCUAGUAUG 8403 CAUACUAGCUUCUGAAUUC 8404 AUUCAGAAGCUAGUAUGGA 8405 UCCAUACUAGCUUCUGAAU 8406 UUCAGAAGCUAGUAUGGAA 8407 UUCCAUACUAGCUUCUGAA 8408 AAAGGUGAUUUGUGUGACA 8409 UGUCACACAAAUCACCUUU 8410 AUUCUGAUUCUGCCACUUC 8411 GAAGUGGCAGAAUCAGAAU 8412 AUUCUGCCACUUCCUGCCU 8413 AGGCAGGAAGUGGCAGAAU 8414 GCCACUUCCUGCCUGUCAA 8415 UUGACAGGCAGGAAGUGGC 8416 CCACUUCCUGCCUGUCAAA 8417 UUUGACAGGCAGGAAGUGG 8418 AACCUUGGGAAGUUGUUCA 8419 UGAACAACUUCCCAAGGUU 8420 ACCUUGGGAAGUUGUUCAA 8421 UUGAACAACUUCCCAAGGU 8422 CCUUGGGAAGUUGUUCAAC 8423 GUUGAACAACUUCCCAAGG 8424 GGGAAGUUGUUCAACCUAC 8425 GUAGGUUGAACAACUUCCC 8426 GGAAGUUGUUCAACCUACC 8427 GGUAGGUUGAACAACUUCC 8428 GAAGUUGUUCAACCUACCA 8429 UGGUAGGUUGAACAACUUC 8430 AAGUUGUUCAACCUACCAA 8431 UUGGUAGGUUGAACAACUU 8432 AGUUGUUCAACCUACCAAA 8433 UUUGGUAGGUUGAACAACU 8434 GUUGUUCAACCUACCAAAA 8435 UUUUGGUAGGUUGAACAAC 8436 GCAAUAAUAAUACAUCACC 8437 GGUGAUGUAUUAUUAUUGC 8438 AUAAUAAUACAUCACCUCC 8439 GGAGGUGAUGUAUUAUUAU 8440 UAAUACAUCACCUCCUAGG 8441 CCUAGGAGGUGAUGUAUUA 8442 AAUACAUCACCUCCUAGGG 8443 CCCUAGGAGGUGAUGUAUU 8444 AUACAUCACCUCCUAGGGU 8445 ACCCUAGGAGGUGAUGUAU 8446 UACAUCACCUCCUAGGGUU 8447 AACCCUAGGAGGUGAUGUA 8448 ACAUCACCUCCUAGGGUUG 8449 CAACCCUAGGAGGUGAUGU 8450 AAAGGAGUAAGAGGAUAAU 8451 AUUAUCCUCUUACUCCUUU 8452 AAGGAGUAAGAGGAUAAUG 8453 CAUUAUCCUCUUACUCCUU 8454 AGUAAGAGGAUAAUGUAGG 8455 CCUACAUUAUCCUCUUACU 8456 GUAAGAGGAUAAUGUAGGU 8457 ACCUACAUUAUCCUCUUAC 8458 UAAGAGGAUAAUGUAGGUA 8459 UACCUACAUUAUCCUCUUA 8460 AAGAGGAUAAUGUAGGUAA 8461 UUACCUACAUUAUCCUCUU 8462 AGAGGAUAAUGUAGGUAAA 8463 UUUACCUACAUUAUCCUCU 8464 GAGGAUAAUGUAGGUAAAG 8465 CUUUACCUACAUUAUCCUC 8466 GGAUAAUGUAGGUAAAGUC 8467 GACUUUACCUACAUUAUCC 8468 AUAAUGUAGGUAAAGUCCU 8469 AGGACUUUACCUACAUUAU 8470 GUAGGUAAAGUCCUCAUAC 8471 GUAUGAGGACUUUACCUAC 8472 GUAAAGUCCUCAUACCUGG 8473 CCAGGUAUGAGGACUUUAC 8474 UAAAGUCCUCAUACCUGGC 8475 GCCAGGUAUGAGGACUUUA 8476 AAAGUCCUCAUACCUGGCA 8477 UGCCAGGUAUGAGGACUUU 8478 AAGUCCUCAUACCUGGCAC 8479 GUGCCAGGUAUGAGGACUU 8480 AGUCCUCAUACCUGGCACA 8481 UGUGCCAGGUAUGAGGACU 8482 GUCCUCAUACCUGGCACAG 8483 CUGUGCCAGGUAUGAGGAC 8484 UCCUCAUACCUGGCACAGA 8485 UCUGUGCCAGGUAUGAGGA 8486 UCUUGAGGGUGUGGGAAGU 8487 ACUUCCCACACCCUCAAGA 8488 CUUGAGGGUGUGGGAAGUG 8489 CACUUCCCACACCCUCAAG 8490 UUGAGGGUGUGGGAAGUGA 8491 UCACUUCCCACACCCUCAA 8492 UGAGGGUGUGGGAAGUGAG 8493 CUCACUUCCCACACCCUCA 8494 AGGGUGUGGGAAGUGAGGU 8495 ACCUCACUUCCCACACCCU 8496 GGGUGUGGGAAGUGAGGUG 8497 CACCUCACUUCCCACACCC 8498 GGGAAGUGAGGUGCAGCAU 8499 AUGCUGCACCUCACUUCCC 8500 GGAAGUGAGGUGCAGCAUU 8501 AAUGCUGCACCUCACUUCC 8502 GAAGUGAGGUGCAGCAUUG 8503 CAAUGCUGCACCUCACUUC 8504 AAGUGAGGUGCAGCAUUGU 8505 ACAAUGCUGCACCUCACUU 8506 AGUGAGGUGCAGCAUUGUA 8507 UACAAUGCUGCACCUCACU 8508 GUGAGGUGCAGCAUUGUAG 8509 CUACAAUGCUGCACCUCAC 8510 UGAGGUGCAGCAUUGUAGA 8511 UCUACAAUGCUGCACCUCA 8512 GAGGUGCAGCAUUGUAGAU 8513 AUCUACAAUGCUGCACCUC 8514 AGGUGCAGCAUUGUAGAUA 8515 UAUCUACAAUGCUGCACCU 8516 GGUGCAGCAUUGUAGAUAA 8517 UUAUCUACAAUGCUGCACC 8518 GUGCAGCAUUGUAGAUAAG 8519 CUUAUCUACAAUGCUGCAC 8520 UGCAGCAUUGUAGAUAAGA 8521 UCUUAUCUACAAUGCUGCA 8522 GCAUUGUAGAUAAGACAGA 8523 UCUGUCUUAUCUACAAUGC 8524 CAUUGUAGAUAAGACAGAA 8525 UUCUGUCUUAUCUACAAUG 8526 AUUGUAGAUAAGACAGAAG 8527 CUUCUGUCUUAUCUACAAU 8528 AUAAGACAGAAGGGUGGAC 8529 GUCCACCCUUCUGUCUUAU 8530 UAAGACAGAAGGGUGGACU 8531 AGUCCACCCUUCUGUCUUA 8532 AACCUGGCUUGCUUUCCAA 8533 UUGGAAAGCAAGCCAGGUU 8534 CCUGGCUUGCUUUCCAAUU 8535 AAUUGGAAAGCAAGCCAGG 8536 ACCAGAAGUGACUUGGAGG 8537 CCUCCAAGUCACUUCUGGU 8538 CCAGAAGUGACUUGGAGGG 8539 CCCUCCAAGUCACUUCUGG 8540 AGAUGCCAAUGACAUGGUA 8541 UACCAUGUCAUUGGCAUCU 8542 GAUGCCAAUGACAUGGUAG 8543 CUACCAUGUCAUUGGCAUC 8544 AUGCCAAUGACAUGGUAGG 8545 CCUACCAUGUCAUUGGCAU 8546 CAAUGACAUGGUAGGAGCA 8547 UGCUCCUACCAUGUCAUUG 8548 AAUGACAUGGUAGGAGCAA 8549 UUGCUCCUACCAUGUCAUU 8550 AUGACAUGGUAGGAGCAAA 8551 UUUGCUCCUACCAUGUCAU 8552 UGACAUGGUAGGAGCAAAG 8553 CUUUGCUCCUACCAUGUCA 8554 GACAUGGUAGGAGCAAAGA 8555 UCUUUGCUCCUACCAUGUC 8556 AAAAGGUCAGCCUCUAGCU 8557 AGCUAGAGGCUGACCUUUU 8558 AAAGGUCAGCCUCUAGCUA 8559 UAGCUAGAGGCUGACCUUU 8560 AGGUCAGCCUCUAGCUAGG 8561 CCUAGCUAGAGGCUGACCU 8562 GGUCAGCCUCUAGCUAGGA 8563 UCCUAGCUAGAGGCUGACC 8564 GUCAGCCUCUAGCUAGGAU 8565 AUCCUAGCUAGAGGCUGAC 8566 CAGCCUCUAGCUAGGAUCC 8567 GGAUCCUAGCUAGAGGCUG 8568 AGCCUCUAGCUAGGAUCCC 8569 GGGAUCCUAGCUAGAGGCU 8570 AGAGCUGCAACCUUUAGGA 8571 UCCUAAAGGUUGCAGCUCU 8572 GAGCUGCAACCUUUAGGAG 8573 CUCCUAAAGGUUGCAGCUC 8574 AGCUGCAACCUUUAGGAGG 8575 CCUCCUAAAGGUUGCAGCU 8576 UUUAGGAGGUAUCAAAGUG 8577 CACUUUGAUACCUCCUAAA 8578 UUAGGAGGUAUCAAAGUGC 8579 GCACUUUGAUACCUCCUAA 8580 UAGGAGGUAUCAAAGUGCC 8581 GGCACUUUGAUACCUCCUA 8582 GUCAAAGUGGGACAUCGAC 8583 GUCGAUGUCCCACUUUGAC 8584 CAUCGACCAAUGUCUAGAG 8585 CUCUAGACAUUGGUCGAUG 8586 AUCGACCAAUGUCUAGAGC 8587 GCUCUAGACAUUGGUCGAU 8588 ACCAAUGUCUAGAGCCAAC 8589 GUUGGCUCUAGACAUUGGU 8590 CAAUGUCUAGAGCCAACUG 8591 CAGUUGGCUCUAGACAUUG 8592 AAUGUCUAGAGCCAACUGA 8593 UCAGUUGGCUCUAGACAUU 8594 AUGUCUAGAGCCAACUGAU 8595 AUCAGUUGGCUCUAGACAU 8596 UGUCUAGAGCCAACUGAUG 8597 CAUCAGUUGGCUCUAGACA 8598 GUCUAGAGCCAACUGAUGG 8599 CCAUCAGUUGGCUCUAGAC 8600 UCUAGAGCCAACUGAUGGA 8601 UCCAUCAGUUGGCUCUAGA 8602 CUAGAGCCAACUGAUGGAU 8603 AUCCAUCAGUUGGCUCUAG 8604 UAGAGCCAACUGAUGGAUG 8605 CAUCCAUCAGUUGGCUCUA 8606 AGAGCCAACUGAUGGAUGU 8607 ACAUCCAUCAGUUGGCUCU 8608 GAGCCAACUGAUGGAUGUU 8609 AACAUCCAUCAGUUGGCUC 8610 AACUGAUGGAUGUUGGGCA 8611 UGCCCAACAUCCAUCAGUU 8612 UGGAUGUUGGGCAGCUAAA 8613 UUUAGCUGCCCAACAUCCA 8614 GGAUGUUGGGCAGCUAAAG 8615 CUUUAGCUGCCCAACAUCC 8616 GAUGUUGGGCAGCUAAAGA 8617 UCUUUAGCUGCCCAACAUC 8618 UUGGGCAGCUAAAGAGGGA 8619 UCCCUCUUUAGCUGCCCAA 8620 UGGGCAGCUAAAGAGGGAA 8621 UUCCCUCUUUAGCUGCCCA 8622 GGGCAGCUAAAGAGGGAAG 8623 CUUCCCUCUUUAGCUGCCC 8624 GGCAGCUAAAGAGGGAAGG 8625 CCUUCCCUCUUUAGCUGCC 8626 GCAGCUAAAGAGGGAAGGG 8627 CCCUUCCCUCUUUAGCUGC 8628 GGGCAUGGGAUAAGACCUG 8629 CAGGUCUUAUCCCAUGCCC 8630 GGCAUGGGAUAAGACCUGC 8631 GCAGGUCUUAUCCCAUGCC 8632 GCAUGGGAUAAGACCUGCC 8633 GGCAGGUCUUAUCCCAUGC 8634 CAUGGGAUAAGACCUGCCC 8635 GGGCAGGUCUUAUCCCAUG 8636 AUGGGAUAAGACCUGCCCU 8637 AGGGCAGGUCUUAUCCCAU 8638 UGGGAUAAGACCUGCCCUU 8639 AAGGGCAGGUCUUAUCCCA 8640 GGGAUAAGACCUGCCCUUC 8641 GAAGGGCAGGUCUUAUCCC 8642 GGAUAAGACCUGCCCUUCU 8643 AGAAGGGCAGGUCUUAUCC 8644 AGACCUGCCCUUCUUGCUU 8645 AAGCAAGAAGGGCAGGUCU 8646 GACCUGCCCUUCUUGCUUC 8647 GAAGCAAGAAGGGCAGGUC 8648 CCUGCCCUUCUUGCUUCUU 8649 AAGAAGCAAGAAGGGCAGG 8650 CUGCCCUUCUUGCUUCUUG 8651 CAAGAAGCAAGAAGGGCAG 8652 UGCCCUUCUUGCUUCUUGC 8653 GCAAGAAGCAAGAAGGGCA 8654 UCUUGCUUCUUGCCAUUGG 8655 CCAAUGGCAAGAAGCAAGA 8656 CUUGCUUCUUGCCAUUGGG 8657 CCCAAUGGCAAGAAGCAAG 8658 UUGCUUCUUGCCAUUGGGC 8659 GCCCAAUGGCAAGAAGCAA 8660 CCAUUGGGCAGGCAUUGGA 8661 UCCAAUGCCUGCCCAAUGG 8662 CAUUGGGCAGGCAUUGGAG 8663 CUCCAAUGCCUGCCCAAUG 8664 GACCCUACUGCUGAAUGGA 8665 UCCAUUCAGCAGUAGGGUC 8666 UACUGCUGAAUGGAGUGCU 8667 AGCACUCCAUUCAGCAGUA 8668 ACUGCUGAAUGGAGUGCUA 8669 UAGCACUCCAUUCAGCAGU 8670 CUGCUGAAUGGAGUGCUAA 8671 UUAGCACUCCAUUCAGCAG 8672 UGCUGAAUGGAGUGCUAAC 8673 GUUAGCACUCCAUUCAGCA 8674 GCUGAAUGGAGUGCUAACC 8675 GGUUAGCACUCCAUUCAGC 8676 CUGAAUGGAGUGCUAACCC 8677 GGGUUAGCACUCCAUUCAG 8678 UAACCCUGGUGCUAGAGGA 8679 UCCUCUAGCACCAGGGUUA 8680 AACCCUGGUGCUAGAGGAG 8681 CUCCUCUAGCACCAGGGUU 8682 ACCCUGGUGCUAGAGGAGG 8683 CCUCCUCUAGCACCAGGGU 8684 CCCUGGUGCUAGAGGAGGA 8685 UCCUCCUCUAGCACCAGGG 8686 CCUGGUGCUAGAGGAGGAU 8687 AUCCUCCUCUAGCACCAGG 8688 CUGGUGCUAGAGGAGGAUG 8689 CAUCCUCCUCUAGCACCAG 8690 GGUGCUAGAGGAGGAUGGA 8691 UCCAUCCUCCUCUAGCACC 8692 GUGCUAGAGGAGGAUGGAA 8693 UUCCAUCCUCCUCUAGCAC 8694 CUGCAGUGGACAGUGAGGA 8695 UCCUCACUGUCCACUGCAG 8696 UGCAGUGGACAGUGAGGAC 8697 GUCCUCACUGUCCACUGCA 8698 GCAGUGGACAGUGAGGACU 8699 AGUCCUCACUGUCCACUGC 8700 CAGUGGACAGUGAGGACUU 8701 AAGUCCUCACUGUCCACUG 8702 AGUGGACAGUGAGGACUUC 8703 GAAGUCCUCACUGUCCACU 8704 GUGGACAGUGAGGACUUCU 8705 AGAAGUCCUCACUGUCCAC 8706 UGGACAGUGAGGACUUCUU 8707 AAGAAGUCCUCACUGUCCA 8708 GGACAGUGAGGACUUCUUC 8709 GAAGAAGUCCUCACUGUCC 8710 AGUGAGGACUUCUUCCAGC 8711 GCUGGAAGAAGUCCUCACU 8712 GUGAGGACUUCUUCCAGCU 8713 AGCUGGAAGAAGUCCUCAC 8714 UGAGGACUUCUUCCAGCUG 8715 CAGCUGGAAGAAGUCCUCA 8716 GAGGACUUCUUCCAGCUGC 8717 GCAGCUGGAAGAAGUCCUC 8718 GUGCCUGAUGGUGUUGCAG 8719 CUGCAACACCAUCAGGCAC 8720 GAUGGUGUUGCAGUCUGGU 8721 ACCAGACUGCAACACCAUC 8722 UGGUGUUGCAGUCUGGUCA 8723 UGACCAGACUGCAACACCA 8724 GGUGUUGCAGUCUGGUCAG 8725 CUGACCAGACUGCAACACC 8726 GUGUUGCAGUCUGGUCAGA 8727 UCUGACCAGACUGCAACAC 8728 UGCAGUCUGGUCAGAGCUG 8729 CAGCUCUGACCAGACUGCA 8730 GCAGUCUGGUCAGAGCUGG 8731 CCAGCUCUGACCAGACUGC 8732 CAGUCUGGUCAGAGCUGGA 8733 UCCAGCUCUGACCAGACUG 8734 AGUCUGGUCAGAGCUGGAG 8735 CUCCAGCUCUGACCAGACU 8736 GUCUGGUCAGAGCUGGAGC 8737 GCUCCAGCUCUGACCAGAC 8738 UCUGGUCAGAGCUGGAGCC 8739 GGCUCCAGCUCUGACCAGA 8740 UGGUCAGAGCUGGAGCCCU 8741 AGGGCUCCAGCUCUGACCA 8742 GGUCAGAGCUGGAGCCCUA 8743 UAGGGCUCCAGCUCUGACC 8744 GUCAGAGCUGGAGCCCUAC 8745 GUAGGGCUCCAGCUCUGAC 8746 CAAGGGUAAGAGGCCUAUA 8747 UAUAGGCCUCUUACCCUUG 8748 AAGGGUAAGAGGCCUAUAC 8749 GUAUAGGCCUCUUACCCUU 8750 AGGGUAAGAGGCCUAUACU 8751 AGUAUAGGCCUCUUACCCU 8752 GGGUAAGAGGCCUAUACUG 8753 CAGUAUAGGCCUCUUACCC 8754 GGUAAGAGGCCUAUACUGG 8755 CCAGUAUAGGCCUCUUACC 8756 GUAAGAGGCCUAUACUGGG 8757 CCCAGUAUAGGCCUCUUAC 8758 GGGCUGCUUCCAAUGCCUG 8759 CAGGCAUUGGAAGCAGCCC 8760 GGCUGCUUCCAAUGCCUGU 8761 ACAGGCAUUGGAAGCAGCC 8762 GCUGCUUCCAAUGCCUGUC 8763 GACAGGCAUUGGAAGCAGC 8764 CUGCUUCCAAUGCCUGUCC 8765 GGACAGGCAUUGGAAGCAG 8766 UGCUUCCAAUGCCUGUCCU 8767 AGGACAGGCAUUGGAAGCA 8768 GCUUCCAAUGCCUGUCCUU 8769 AAGGACAGGCAUUGGAAGC 8770 CUUCCAAUGCCUGUCCUUU 8771 AAAGGACAGGCAUUGGAAG 8772 UUCCAAUGCCUGUCCUUUA 8773 UAAAGGACAGGCAUUGGAA 8774 UCCAAUGCCUGUCCUUUAG 8775 CUAAAGGACAGGCAUUGGA 8776 CAAUGCCUGUCCUUUAGAG 8777 CUCUAAAGGACAGGCAUUG 8778 AAUGCCUGUCCUUUAGAGC 8779 GCUCUAAAGGACAGGCAUU 8780 AUGCCUGUCCUUUAGAGCU 8781 AGCUCUAAAGGACAGGCAU 8782 CUUCCUCUCUAGCUUAACC 8783 GGUUAAGCUAGAGAGGAAG 8784 UUCCUCUCUAGCUUAACCC 8785 GGGUUAAGCUAGAGAGGAA 8786 UCUCUAGCUUAACCCUGAU 8787 AUCAGGGUUAAGCUAGAGA 8788 UAGCUUAACCCUGAUCCUG 8789 CAGGAUCAGGGUUAAGCUA 8790 GACCAGGUGCAGGAGGAGU 8791 ACUCCUCCUGCACCUGGUC 8792 ACCAGGUGCAGGAGGAGUU 8793 AACUCCUCCUGCACCUGGU 8794 CCAGGUGCAGGAGGAGUUG 8795 CAACUCCUCCUGCACCUGG 8796 CAGGUGCAGGAGGAGUUGU 8797 ACAACUCCUCCUGCACCUG 8798 AGGUGCAGGAGGAGUUGUG 8799 CACAACUCCUCCUGCACCU 8800 UGCAGGAGGAGUUGUGGAA 8801 UUCCACAACUCCUCCUGCA 8802 GCAGGAGGAGUUGUGGAAU 8803 AUUCCACAACUCCUCCUGC 8804 AGGAGGAGUUGUGGAAUUG 8805 CAAUUCCACAACUCCUCCU 8806 GGAGGAGUUGUGGAAUUGU 8807 ACAAUUCCACAACUCCUCC 8808 GAGGAGUUGUGGAAUUGUC 8809 GACAAUUCCACAACUCCUC 8810 AGGAGUUGUGGAAUUGUCA 8811 UGACAAUUCCACAACUCCU 8812 GGAGUUGUGGAAUUGUCAA 8813 UUGACAAUUCCACAACUCC 8814 GAGUUGUGGAAUUGUCAAG 8815 CUUGACAAUUCCACAACUC 8816 AGUUGUGGAAUUGUCAAGG 8817 CCUUGACAAUUCCACAACU 8818 GUUGUGGAAUUGUCAAGGA 8819 UCCUUGACAAUUCCACAAC 8820 UGGAAUUGUCAAGGAUGUC 8821 GACAUCCUUGACAAUUCCA 8822 GGAAUUGUCAAGGAUGUCA 8823 UGACAUCCUUGACAAUUCC 8824 AGUCCAAGCGAGGGAGGGU 8825 ACCCUCCCUCGCUUGGACU 8826 CAAGCGAGGGAGGGUCUGA 8827 UCAGACCCUCCCUCGCUUG 8828 AAGCGAGGGAGGGUCUGAC 8829 GUCAGACCCUCCCUCGCUU 8830 CUGACCCAGUGCUGAUGGA 8831 UCCAUCAGCACUGGGUCAG 8832 AGAUUAGUGGUGGGUGUCU 8833 AGACACCCACCACUAAUCU 8834 AUUAGUGGUGGGUGUCUGG 8835 CCAGACACCCACCACUAAU 8836 UUAGUGGUGGGUGUCUGGU 8837 ACCAGACACCCACCACUAA 8838 UAGUGGUGGGUGUCUGGUA 8839 UACCAGACACCCACCACUA 8840 AGUGGUGGGUGUCUGGUAU 8841 AUACCAGACACCCACCACU 8842 GUGGUGGGUGUCUGGUAUG 8843 CAUACCAGACACCCACCAC 8844 UGGUGGGUGUCUGGUAUGA 8845 UCAUACCAGACACCCACCA 8846 GGUGGGUGUCUGGUAUGAG 8847 CUCAUACCAGACACCCACC 8848 GUGGGUGUCUGGUAUGAGG 8849 CCUCAUACCAGACACCCAC 8850 UGGGUGUCUGGUAUGAGGA 8851 UCCUCAUACCAGACACCCA 8852 GGGUGUCUGGUAUGAGGAU 8853 AUCCUCAUACCAGACACCC 8854 GGUGUCUGGUAUGAGGAUC 8855 GAUCCUCAUACCAGACACC 8856 GUGUCUGGUAUGAGGAUCU 8857 AGAUCCUCAUACCAGACAC 8858 UGUCUGGUAUGAGGAUCUA 8859 UAGAUCCUCAUACCAGACA 8860 CAAGGGUGUCCUACAGAGU 8861 ACUCUGUAGGACACCCUUG 8862 AAGGGUGUCCUACAGAGUG 8863 CACUCUGUAGGACACCCUU 8864 AGGGUGUCCUACAGAGUGG 8865 CCACUCUGUAGGACACCCU 8866 GGGUGUCCUACAGAGUGGA 8867 UCCACUCUGUAGGACACCC 8868 GGUGUCCUACAGAGUGGAG 8869 CUCCACUCUGUAGGACACC 8870 UCCUACAGAGUGGAGUGCU 8871 AGCACUCCACUCUGUAGGA 8872 AGUGGAGUGCUGUCAUAUG 8873 CAUAUGACAGCACUCCACU 8874 GUGGAGUGCUGUCAUAUGG 8875 CCAUAUGACAGCACUCCAC 8876 UGGAGUGCUGUCAUAUGGC 8877 GCCAUAUGACAGCACUCCA 8878 GGAGUGCUGUCAUAUGGCC 8879 GGCCAUAUGACAGCACUCC 8880 GAGUGCUGUCAUAUGGCCU 8881 AGGCCAUAUGACAGCACUC 8882 AGUGCUGUCAUAUGGCCUG 8883 CAGGCCAUAUGACAGCACU 8884 GUGCUGUCAUAUGGCCUGG 8885 CCAGGCCAUAUGACAGCAC 8886 UGCUGUCAUAUGGCCUGGG 8887 CCCAGGCCAUAUGACAGCA 8888 GCUGUCAUAUGGCCUGGGA 8889 UCCCAGGCCAUAUGACAGC 8890 CUGUCAUAUGGCCUGGGAC 8891 GUCCCAGGCCAUAUGACAG 8892 UGUCAUAUGGCCUGGGACG 8893 CGUCCCAGGCCAUAUGACA 8894 GUCAUAUGGCCUGGGACGG 8895 CCGUCCCAGGCCAUAUGAC 8896 AGAGGCCCAAGCACAGCAA 8897 UUGCUGUGCUUGGGCCUCU 8898 GAGGCCCAAGCACAGCAAG 8899 CUUGCUGUGCUUGGGCCUC 8900 AGGCCCAAGCACAGCAAGG 8901 CCUUGCUGUGCUUGGGCCU 8902 GGCCCAAGCACAGCAAGGA 8903 UCCUUGCUGUGCUUGGGCC 8904 CCAAGCACAGCAAGGACAU 8905 AUGUCCUUGCUGUGCUUGG 8906 GCCCGAUUCACCUUUGACG 8907 CGUCAAAGGUGAAUCGGGC 8908 GAUUCACCUUUGACGUGUA 8909 UACACGUCAAAGGUGAAUC 8910 AUUCACCUUUGACGUGUAC 8911 GUACACGUCAAAGGUGAAU 8912 UUGGCAGCCUGAAUGUCAA 8913 UUGACAUUCAGGCUGCCAA 8914 UGGCAGCCUGAAUGUCAAA 8915 UUUGACAUUCAGGCUGCCA 8916 GGCAGCCUGAAUGUCAAAG 8917 CUUUGACAUUCAGGCUGCC 8918 GCAGCCUGAAUGUCAAAGC 8919 GCUUUGACAUUCAGGCUGC 8920 CAGCCUGAAUGUCAAAGCC 8921 GGCUUUGACAUUCAGGCUG 8922 AGCCUGAAUGUCAAAGCCA 8923 UGGCUUUGACAUUCAGGCU 8924 GCCUGAAUGUCAAAGCCAC 8925 GUGGCUUUGACAUUCAGGC 8926 GUCAAAGCCACAUUCUACG 8927 CGUAGAAUGUGGCUUUGAC 8928 UCAAAGCCACAUUCUACGG 8929 CCGUAGAAUGUGGCUUUGA 8930 CAAAGCCACAUUCUACGGG 8931 CCCGUAGAAUGUGGCUUUG 8932 AAAGCCACAUUCUACGGGC 8933 GCCCGUAGAAUGUGGCUUU 8934 GCCACAUUCUACGGGCUCU 8935 AGAGCCCGUAGAAUGUGGC 8936 CCACAUUCUACGGGCUCUA 8937 UAGAGCCCGUAGAAUGUGG 8938 CACAUUCUACGGGCUCUAC 8939 GUAGAGCCCGUAGAAUGUG 8940 UUCUACGGGCUCUACUCUA 8941 UAGAGUAGAGCCCGUAGAA 8942 UCUACGGGCUCUACUCUAU 8943 AUAGAGUAGAGCCCGUAGA 8944 CUACGGGCUCUACUCUAUG 8945 CAUAGAGUAGAGCCCGUAG 8946 CUCUAUGAGUUGUGACUUU 8947 AAAGUCACAACUCAUAGAG 8948 UCUAUGAGUUGUGACUUUC 8949 GAAAGUCACAACUCAUAGA 8950 UGAGUUGUGACUUUCAAGG 8951 CCUUGAAAGUCACAACUCA 8952 GAGUUGUGACUUUCAAGGA 8953 UCCUUGAAAGUCACAACUC 8954 AGUUGUGACUUUCAAGGAC 8955 GUCCUUGAAAGUCACAACU 8956 GUUGUGACUUUCAAGGACU 8957 AGUCCUUGAAAGUCACAAC 8958 GACUUUCAAGGACUUGGCC 8959 GGCCAAGUCCUUGAAAGUC 8960 UUUCAAGGACUUGGCCCAA 8961 UUGGGCCAAGUCCUUGAAA 8962 UUCAAGGACUUGGCCCAAA 8963 UUUGGGCCAAGUCCUUGAA 8964 CCCUACAGUUGGAUAGUCC 8965 GGACUAUCCAACUGUAGGG 8966 CCUACAGUUGGAUAGUCCC 8967 GGGACUAUCCAACUGUAGG 8968 AUUCGUCCUCUUGCACCCA 8969 UGGGUGCAAGAGGACGAAU 8970 UUCGUCCUCUUGCACCCAC 8971 GUGGGUGCAAGAGGACGAA 8972 UCCUCUUGCACCCACCUAC 8973 GUAGGUGGGUGCAAGAGGA 8974 CCUCUUGCACCCACCUACC 8975 GGUAGGUGGGUGCAAGAGG 8976 CUCUUGCACCCACCUACCC 8977 GGGUAGGUGGGUGCAAGAG 8978 CUAGUUAGCUCUUGCUUGU 8979 ACAAGCAAGAGCUAACUAG 8980 UAGUUAGCUCUUGCUUGUG 8981 CACAAGCAAGAGCUAACUA 8982 AGUUAGCUCUUGCUUGUGG 8983 CCACAAGCAAGAGCUAACU 8984 UUAGCUCUUGCUUGUGGAA 8985 UUCCACAAGCAAGAGCUAA 8986 UCCUCAUCUCCCAGCUUGA 8987 UCAAGCUGGGAGAUGAGGA 8988 AUCUCCCAGCUUGAUGGCU 8989 AGCCAUCAAGCUGGGAGAU 8990 UCUCCCAGCUUGAUGGCUU 8991 AAGCCAUCAAGCUGGGAGA 8992 CUCCCAGCUUGAUGGCUUC 8993 GAAGCCAUCAAGCUGGGAG 8994 UCCCAGCUUGAUGGCUUCC 8995 GGAAGCCAUCAAGCUGGGA 8996 CCCAGCUUGAUGGCUUCCU 8997 AGGAAGCCAUCAAGCUGGG 8998 CCAGCUUGAUGGCUUCCUC 8999 GAGGAAGCCAUCAAGCUGG 9000 UGAUGGCUUCCUCCCAAGU 9001 ACUUGGGAGGAAGCCAUCA 9002 GAUGGCUUCCUCCCAAGUU 9003 AACUUGGGAGGAAGCCAUC 9004 GGCUUCCUCCCAAGUUUUC 9005 GAAAACUUGGGAGGAAGCC 9006 CCUCCCAAGUUUUCCAAAU 9007 AUUUGGAAAACUUGGGAGG 9008 CCCAAGUUUUCCAAAUCAU 9009 AUGAUUUGGAAAACUUGGG 9010 CCAAGUUUUCCAAAUCAUC 9011 GAUGAUUUGGAAAACUUGG 9012 CAAGUUUUCCAAAUCAUCU 9013 AGAUGAUUUGGAAAACUUG 9014 AAGUUUUCCAAAUCAUCUG 9015 CAGAUGAUUUGGAAAACUU 9016 GUUUUCCAAAUCAUCUGAU 9017 AUCAGAUGAUUUGGAAAAC 9018 AUCUGAUUUCCUCUUGUCU 9019 AGACAAGAGGAAAUCAGAU 9020 UCUGAUUUCCUCUUGUCUC 9021 GAGACAAGAGGAAAUCAGA 9022 CUGAUUUCCUCUUGUCUCU 9023 AGAGACAAGAGGAAAUCAG 9024 CUCUUGUCUCUGCCAUUCA 9025 UGAAUGGCAGAGACAAGAG 9026 GUUGGACCUCCACACUGCU 9027 AGCAGUGUGGAGGUCCAAC 9028 CCACACUGCUGCAAGGCCU 9029 AGGCCUUGCAGCAGUGUGG 9030 CACACUGCUGCAAGGCCUG 9031 CAGGCCUUGCAGCAGUGUG 9032 ACACUGCUGCAAGGCCUGG 9033 CCAGGCCUUGCAGCAGUGU 9034 UGCAAGGCCUGGGCCAUAU 9035 AUAUGGCCCAGGCCUUGCA 9036 GCAAGGCCUGGGCCAUAUG 9037 CAUAUGGCCCAGGCCUUGC 9038 CAAGGCCUGGGCCAUAUGU 9039 ACAUAUGGCCCAGGCCUUG 9040 AAGGCCUGGGCCAUAUGUU 9041 AACAUAUGGCCCAGGCCUU 9042 AGGCCUGGGCCAUAUGUUG 9043 CAACAUAUGGCCCAGGCCU 9044 GGCCUGGGCCAUAUGUUGC 9045 GCAACAUAUGGCCCAGGCC 9046 GCCUGGGCCAUAUGUUGCU 9047 AGCAACAUAUGGCCCAGGC 9048 CCUGGGCCAUAUGUUGCUG 9049 CAGCAACAUAUGGCCCAGG 9050 GGCCAUAUGUUGCUGGGAA 9051 UUCCCAGCAACAUAUGGCC 9052 CCAUAUGUUGCUGGGAAUU 9053 AAUUCCCAGCAACAUAUGG 9054 GGAAUUUCCUCCACCCUUC 9055 GAAGGGUGGAGGAAAUUCC 9056 GAAUUUCCUCCACCCUUCG 9057 CGAAGGGUGGAGGAAAUUC 9058 AAUUUCCUCCACCCUUCGU 9059 ACGAAGGGUGGAGGAAAUU 9060 AUUUCCUCCACCCUUCGUC 9061 GACGAAGGGUGGAGGAAAU 9062 UUUCCUCCACCCUUCGUCA 9063 UGACGAAGGGUGGAGGAAA 9064 UUCCUCCACCCUUCGUCAU 9065 AUGACGAAGGGUGGAGGAA 9066 UCCUCCACCCUUCGUCAUG 9067 CAUGACGAAGGGUGGAGGA 9068 CCUCCACCCUUCGUCAUGC 9069 GCAUGACGAAGGGUGGAGG 9070 CUCCACCCUUCGUCAUGCA 9071 UGCAUGACGAAGGGUGGAG 9072 CCUUCGUCAUGCAGUGGAG 9073 CUCCACUGCAUGACGAAGG 9074 CUUCGUCAUGCAGUGGAGG 9075 CCUCCACUGCAUGACGAAG 9076 UUCGUCAUGCAGUGGAGGG 9077 CCCUCCACUGCAUGACGAA 9078 CGCCUCCAUUCCUACUAAG 9079 CUUAGUAGGAAUGGAGGCG 9080 GCCUCCAUUCCUACUAAGG 9081 CCUUAGUAGGAAUGGAGGC 9082 CCUCCAUUCCUACUAAGGG 9083 CCCUUAGUAGGAAUGGAGG 9084 CAGAAUCAUUCCAACCGAC 9085 GUCGGUUGGAAUGAUUCUG 9086 AGAAUCAUUCCAACCGACC 9087 GGUCGGUUGGAAUGAUUCU 9088 GAAUCAUUCCAACCGACCC 9089 GGGUCGGUUGGAAUGAUUC 9090 AAUCAUUCCAACCGACCCA 9091 UGGGUCGGUUGGAAUGAUU 9092 AUCAUUCCAACCGACCCAC 9093 GUGGGUCGGUUGGAAUGAU 9094 UCAUUCCAACCGACCCACU 9095 AGUGGGUCGGUUGGAAUGA 9096 UCCAACCGACCCACUGCAA 9097 UUGCAGUGGGUCGGUUGGA 9098 CCAACCGACCCACUGCAAA 9099 UUUGCAGUGGGUCGGUUGG 9100 CAACCGACCCACUGCAAAG 9101 CUUUGCAGUGGGUCGGUUG 9102 AACCGACCCACUGCAAAGA 9103 UCUUUGCAGUGGGUCGGUU 9104 ACCGACCCACUGCAAAGAC 9105 GUCUUUGCAGUGGGUCGGU 9106 CCGACCCACUGCAAAGACU 9107 AGUCUUUGCAGUGGGUCGG 9108 CGACCCACUGCAAAGACUA 9109 UAGUCUUUGCAGUGGGUCG 9110 GACCCACUGCAAAGACUAU 9111 AUAGUCUUUGCAGUGGGUC 9112 ACCCACUGCAAAGACUAUG 9113 CAUAGUCUUUGCAGUGGGU 9114 ACUGCAAAGACUAUGACAG 9115 CUGUCAUAGUCUUUGCAGU 9116 CUGCAAAGACUAUGACAGC 9117 GCUGUCAUAGUCUUUGCAG 9118 UGCAAAGACUAUGACAGCA 9119 UGCUGUCAUAGUCUUUGCA 9120 GCAAAGACUAUGACAGCAU 9121 AUGCUGUCAUAGUCUUUGC 9122 AAAGACUAUGACAGCAUCA 9123 UGAUGCUGUCAUAGUCUUU 9124 AAGACUAUGACAGCAUCAA 9125 UUGAUGCUGUCAUAGUCUU 9126 AGACUAUGACAGCAUCAAA 9127 UUUGAUGCUGUCAUAGUCU 9128 GACUAUGACAGCAUCAAAU 9129 AUUUGAUGCUGUCAUAGUC 9130 CUAUGACAGCAUCAAAUUU 9131 AAAUUUGAUGCUGUCAUAG 9132 UAUGACAGCAUCAAAUUUC 9133 GAAAUUUGAUGCUGUCAUA 9134 GCAUCAAAUUUCAGGACCU 9135 AGGUCCUGAAAUUUGAUGC 9136 AUCAAAUUUCAGGACCUGC 9137 GCAGGUCCUGAAAUUUGAU 9138 UCAAAUUUCAGGACCUGCA 9139 UGCAGGUCCUGAAAUUUGA 9140 UUCAGGACCUGCAGACAGU 9141 ACUGUCUGCAGGUCCUGAA 9142 UCAGGACCUGCAGACAGUA 9143 UACUGUCUGCAGGUCCUGA 9144 CAGGACCUGCAGACAGUAC 9145 GUACUGUCUGCAGGUCCUG 9146 AGGACCUGCAGACAGUACA 9147 UGUACUGUCUGCAGGUCCU 9148 GGACCUGCAGACAGUACAG 9149 CUGUACUGUCUGCAGGUCC 9150 CUGCAGACAGUACAGGCUA 9151 UAGCCUGUACUGUCUGCAG 9152 GACAGUACAGGCUAGAUAA 9153 UUAUCUAGCCUGUACUGUC 9154 ACAGUACAGGCUAGAUAAC 9155 GUUAUCUAGCCUGUACUGU 9156 CAGUACAGGCUAGAUAACC 9157 GGUUAUCUAGCCUGUACUG 9158 AGUACAGGCUAGAUAACCC 9159 GGGUUAUCUAGCCUGUACU 9160 GUACAGGCUAGAUAACCCA 9161 UGGGUUAUCUAGCCUGUAC 9162 UACAGGCUAGAUAACCCAC 9163 GUGGGUUAUCUAGCCUGUA 9164 GCUAGAUAACCCACCCAAU 9165 AUUGGGUGGGUUAUCUAGC 9166 CUAGAUAACCCACCCAAUU 9167 AAUUGGGUGGGUUAUCUAG 9168 AGAUAACCCACCCAAUUUC 9169 GAAAUUGGGUGGGUUAUCU 9170 GAUAACCCACCCAAUUUCC 9171 GGAAAUUGGGUGGGUUAUC 9172 AACCUUUCAGCAUAACGCC 9173 GGCGUUAUGCUGAAAGGUU 9174 ACCUUUCAGCAUAACGCCU 9175 AGGCGUUAUGCUGAAAGGU 9176 CCUUUCAGCAUAACGCCUC 9177 GAGGCGUUAUGCUGAAAGG 9178 CUUUCAGCAUAACGCCUCA 9179 UGAGGCGUUAUGCUGAAAG 9180 UUUCAGCAUAACGCCUCAC 9181 GUGAGGCGUUAUGCUGAAA 9182 UUCAGCAUAACGCCUCACA 9183 UGUGAGGCGUUAUGCUGAA 9184 UCAGCAUAACGCCUCACAU 9185 AUGUGAGGCGUUAUGCUGA 9186 CAGCAUAACGCCUCACAUC 9187 GAUGUGAGGCGUUAUGCUG 9188 AGCAUAACGCCUCACAUCC 9189 GGAUGUGAGGCGUUAUGCU 9190 GCAUAACGCCUCACAUCCC 9191 GGGAUGUGAGGCGUUAUGC 9192 AACGCCUCACAUCCCAAGU 9193 ACUUGGGAUGUGAGGCGUU 9194 ACGCCUCACAUCCCAAGUC 9195 GACUUGGGAUGUGAGGCGU 9196 CGCCUCACAUCCCAAGUCU 9197 AGACUUGGGAUGUGAGGCG 9198 UCACAUCCCAAGUCUAUAC 9199 GUAUAGACUUGGGAUGUGA 9200 CACAUCCCAAGUCUAUACC 9201 GGUAUAGACUUGGGAUGUG 9202 ACAUCCCAAGUCUAUACCC 9203 GGGUAUAGACUUGGGAUGU 9204 CAUCCCAAGUCUAUACCCU 9205 AGGGUAUAGACUUGGGAUG 9206 AAUGCUGUUCUUUCCUAGC 9207 GCUAGGAAAGAACAGCAUU 9208 AUGCUGUUCUUUCCUAGCC 9209 GGCUAGGAAAGAACAGCAU 9210 CUGUUCUUUCCUAGCCACC 9211 GGUGGCUAGGAAAGAACAG 9212 UGUUCUUUCCUAGCCACCU 9213 AGGUGGCUAGGAAAGAACA 9214 GCCAAGAUCAAGAUGUCCC 9215 GGGACAUCUUGAUCUUGGC 9216 UCUUGAUCCCAGCCUGACU 9217 AGUCAGGCUGGGAUCAAGA 9218 CUUGAUCCCAGCCUGACUG 9219 CAGUCAGGCUGGGAUCAAG 9220 UUGAUCCCAGCCUGACUGC 9221 GCAGUCAGGCUGGGAUCAA 9222 UGAUCCCAGCCUGACUGCU 9223 AGCAGUCAGGCUGGGAUCA 9224 CUGACUGCUGCUACAUCUA 9225 UAGAUGUAGCAGCAGUCAG 9226 GACUGCUGCUACAUCUAAU 9227 AUUAGAUGUAGCAGCAGUC 9228 ACUGCUGCUACAUCUAAUC 9229 GAUUAGAUGUAGCAGCAGU 9230 CUGCUGCUACAUCUAAUCC 9231 GGAUUAGAUGUAGCAGCAG 9232 UGCUGCUACAUCUAAUCCC 9233 GGGAUUAGAUGUAGCAGCA 9234 CCUACCAAUGCCUCCUGUC 9235 GACAGGAGGCAUUGGUAGG 9236 CUACCAAUGCCUCCUGUCC 9237 GGACAGGAGGCAUUGGUAG 9238 CCAAUGCCUCCUGUCCCUA 9239 UAGGGACAGGAGGCAUUGG 9240 CAAUGCCUCCUGUCCCUAA 9241 UUAGGGACAGGAGGCAUUG 9242 AAUGCCUCCUGUCCCUAAA 9243 UUUAGGGACAGGAGGCAUU 9244 CCCAGCAUACUGAUGACAG 9245 CUGUCAUCAGUAUGCUGGG 9246 CCAGCAUACUGAUGACAGC 9247 GCUGUCAUCAGUAUGCUGG 9248 CAUACUGAUGACAGCCCUC 9249 GAGGGCUGUCAUCAGUAUG 9250 AUACUGAUGACAGCCCUCU 9251 AGAGGGCUGUCAUCAGUAU 9252 UACUGAUGACAGCCCUCUC 9253 GAGAGGGCUGUCAUCAGUA 9254 ACUGAUGACAGCCCUCUCU 9255 AGAGAGGGCUGUCAUCAGU 9256 CUGAUGACAGCCCUCUCUG 9257 CAGAGAGGGCUGUCAUCAG 9258 UGAUGACAGCCCUCUCUGA 9259 UCAGAGAGGGCUGUCAUCA 9260 GAUGACAGCCCUCUCUGAC 9261 GUCAGAGAGGGCUGUCAUC 9262 AUGACAGCCCUCUCUGACU 9263 AGUCAGAGAGGGCUGUCAU 9264 UGACAGCCCUCUCUGACUU 9265 AAGUCAGAGAGGGCUGUCA 9266 GACAGCCCUCUCUGACUUU 9267 AAAGUCAGAGAGGGCUGUC 9268 ACAGCCCUCUCUGACUUUA 9269 UAAAGUCAGAGAGGGCUGU 9270 CAGCCCUCUCUGACUUUAC 9271 GUAAAGUCAGAGAGGGCUG 9272 AGCCCUCUCUGACUUUACC 9273 GGUAAAGUCAGAGAGGGCU 9274 GCCCUCUCUGACUUUACCU 9275 AGGUAAAGUCAGAGAGGGC 9276 CCCUCUCUGACUUUACCUU 9277 AAGGUAAAGUCAGAGAGGG 9278 CCUCUCUGACUUUACCUUG 9279 CAAGGUAAAGUCAGAGAGG 9280 CUCUCUGACUUUACCUUGA 9281 UCAAGGUAAAGUCAGAGAG 9282 AGAUCUGUCUUCAUACCCU 9283 AGGGUAUGAAGACAGAUCU 9284 GAUCUGUCUUCAUACCCUU 9285 AAGGGUAUGAAGACAGAUC 9286 CUGUCUUCAUACCCUUCCC 9287 GGGAAGGGUAUGAAGACAG 9288 UAUUUACCACUAAGACUUC 9289 GAAGUCUUAGUGGUAAAUA 9290 AUUUACCACUAAGACUUCU 9291 AGAAGUCUUAGUGGUAAAU 9292 UUUACCACUAAGACUUCUG 9293 CAGAAGUCUUAGUGGUAAA 9294 UUACCACUAAGACUUCUGA 9295 UCAGAAGUCUUAGUGGUAA 9296 UACCACUAAGACUUCUGAC 9297 GUCAGAAGUCUUAGUGGUA 9298 ACCACUAAGACUUCUGACU 9299 AGUCAGAAGUCUUAGUGGU 9300 ACUUCUGACUCCAAUUUAA 9301 UUAAAUUGGAGUCAGAAGU 9302 CUUCUGACUCCAAUUUAAA 9303 UUUAAAUUGGAGUCAGAAG 9304 ACACCCAGUCCCAGAUCCA 9305 UGGAUCUGGGACUGGGUGU 9306 CACCCAGUCCCAGAUCCAA 9307 UUGGAUCUGGGACUGGGUG 9308 ACCCAGUCCCAGAUCCAAA 9309 UUUGGAUCUGGGACUGGGU 9310

In some embodiments, the siRNA molecules targeted to Transcript D comprise or consist of the nucleotide sequences (sense and antisense strands) shown in Table 11.

TABLE 11 SEQ SEQ ID ID Sense Sequence NO: Antisense Sequence NO: UUCCAGCUCAGCAGUGUCU 9311 AGACACUGCUGAGCUGGAA 9312 UCCAGCUCAGCAGUGUCUC 9313 GAGACACUGCUGAGCUGGA 9314 CCAGCUCAGCAGUGUCUCG 9315 CGAGACACUGCUGAGCUGG 9316 CAGCUCAGCAGUGUCUCGU 9317 ACGAGACACUGCUGAGCUG 9318 AGCUCAGCAGUGUCUCGUU 9319 AACGAGACACUGCUGAGCU 9320 GCUCAGCAGUGUCUCGUUC 9321 GAACGAGACACUGCUGAGC 9322 CUCAGCAGUGUCUCGUUCC 9323 GGAACGAGACACUGCUGAG 9324 GUAGCAGACCGACAUCCUU 9325 AAGGAUGUCGGUCUGCUAC 9326 UAGCAGACCGACAUCCUUC 9327 GAAGGAUGUCGGUCUGCUA 9328 AGCAGACCGACAUCCUUCU 9329 AGAAGGAUGUCGGUCUGCU 9330 AGACCGACAUCCUUCUGGG 9331 CCCAGAAGGAUGUCGGUCU 9332 GACCGACAUCCUUCUGGGC 9333 GCCCAGAAGGAUGUCGGUC 9334 CCGACAUCCUUCUGGGCCU 9335 AGGCCCAGAAGGAUGUCGG 9336 CGACAUCCUUCUGGGCCUA 9337 UAGGCCCAGAAGGAUGUCG 9338 GACAUCCUUCUGGGCCUAC 9339 GUAGGCCCAGAAGGAUGUC 9340 CUUCUGGGCCUACAGGUGG 9341 CCACCUGUAGGCCCAGAAG 9342 UUCUGGGCCUACAGGUGGG 9343 CCCACCUGUAGGCCCAGAA 9344 UCUGGGCCUACAGGUGGGU 9345 ACCCACCUGUAGGCCCAGA 9346 GGCCUACAGGUGGGUGGAA 9347 UUCCACCCACCUGUAGGCC 9348 CCUACAGGUGGGUGGAAGG 9349 CCUUCCACCCACCUGUAGG 9350 CUACAGGUGGGUGGAAGGC 9351 GCCUUCCACCCACCUGUAG 9352 UACAGGUGGGUGGAAGGCG 9353 CGCCUUCCACCCACCUGUA 9354 ACUUCCCUGCAGCCUGCCU 9355 AGGCAGGCUGCAGGGAAGU 9356 CCUGCAGCCUGCCUCUUUU 9357 AAAAGAGGCAGGCUGCAGG 9358 CUGCAGCCUGCCUCUUUUC 9359 GAAAAGAGGCAGGCUGCAG 9360 GCAGCCUGCCUCUUUUCUG 9361 CAGAAAAGAGGCAGGCUGC 9362 CAGCCUGCCUCUUUUCUGC 9363 GCAGAAAAGAGGCAGGCUG 9364 AGCCUGCCUCUUUUCUGCC 9365 GGCAGAAAAGAGGCAGGCU 9366 GCCUCUUUUCUGCCUGGGA 9367 UCCCAGGCAGAAAAGAGGC 9368 CUUUUCUGCCUGGGAGUCC 9369 GGACUCCCAGGCAGAAAAG 9370 UUUUCUGCCUGGGAGUCCU 9371 AGGACUCCCAGGCAGAAAA 9372 UUCUGCCUGGGAGUCCUGA 9373 UCAGGACUCCCAGGCAGAA 9374 UCUGCCUGGGAGUCCUGAC 9375 GUCAGGACUCCCAGGCAGA 9376 UGCCUGGGAGUCCUGACUU 9377 AAGUCAGGACUCCCAGGCA 9378 GCCUGGGAGUCCUGACUUC 9379 GAAGUCAGGACUCCCAGGC 9380 CUGGGAGUCCUGACUUCCA 9381 UGGAAGUCAGGACUCCCAG 9382 UGGGAGUCCUGACUUCCAC 9383 GUGGAAGUCAGGACUCCCA 9384 GGGAGUCCUGACUUCCACG 9385 CGUGGAAGUCAGGACUCCC 9386 GGAGUCCUGACUUCCACGA 9387 UCGUGGAAGUCAGGACUCC 9388 GAGUCCUGACUUCCACGAG 9389 CUCGUGGAAGUCAGGACUC 9390 AGUCCUGACUUCCACGAGG 9391 CCUCGUGGAAGUCAGGACU 9392 CCUGACUUCCACGAGGACC 9393 GGUCCUCGUGGAAGUCAGG 9394 CUGACUUCCACGAGGACCC 9395 GGGUCCUCGUGGAAGUCAG 9396 UGACUUCCACGAGGACCCA 9397 UGGGUCCUCGUGGAAGUCA 9398 GACUUCCACGAGGACCCAG 9399 CUGGGUCCUCGUGGAAGUC 9400 ACUUCCACGAGGACCCAGA 9401 UCUGGGUCCUCGUGGAAGU 9402 CUUCCACGAGGACCCAGAC 9403 GUCUGGGUCCUCGUGGAAG 9404 UUCCACGAGGACCCAGACC 9405 GGUCUGGGUCCUCGUGGAA 9406 CCCUGCUCCCAGUCAGUUG 9407 CAACUGACUGGGAGCAGGG 9408 CCUGCUCCCAGUCAGUUGA 9409 UCAACUGACUGGGAGCAGG 9410 CUGCUCCCAGUCAGUUGAC 9411 GUCAACUGACUGGGAGCAG 9412 UGCUCCCAGUCAGUUGACC 9413 GGUCAACUGACUGGGAGCA 9414 CCCAGUCAGUUGACCUGCC 9415 GGCAGGUCAACUGACUGGG 9416 CCAGUCAGUUGACCUGCCC 9417 GGGCAGGUCAACUGACUGG 9418 GCCUCCUUCCCAGAGCUCA 9419 UGAGCUCUGGGAAGGAGGC 9420 CCUCCUUCCCAGAGCUCAG 9421 CUGAGCUCUGGGAAGGAGG 9422 CUCCUUCCCAGAGCUCAGU 9423 ACUGAGCUCUGGGAAGGAG 9424 UCCUUCCCAGAGCUCAGUG 9425 CACUGAGCUCUGGGAAGGA 9426 CCUUCCCAGAGCUCAGUGG 9427 CCACUGAGCUCUGGGAAGG 9428 UUCCCAGAGCUCAGUGGUA 9429 UACCACUGAGCUCUGGGAA 9430 UCCCAGAGCUCAGUGGUAA 9431 UUACCACUGAGCUCUGGGA 9432 CAGGCUGUCACUAUCUCUA 9433 UAGAGAUAGUGACAGCCUG 9434 AGGCUGUCACUAUCUCUAC 9435 GUAGAGAUAGUGACAGCCU 9436 UCUCUACCACCACUCCUCU 9437 AGAGGAGUGGUGGUAGAGA 9438 CCACCACUCCUCUAGUCUG 9439 CAGACUAGAGGAGUGGUGG 9440 CACCACUCCUCUAGUCUGG 9441 CCAGACUAGAGGAGUGGUG 9442 ACCACUCCUCUAGUCUGGC 9443 GCCAGACUAGAGGAGUGGU 9444 CCACUCCUCUAGUCUGGCC 9445 GGCCAGACUAGAGGAGUGG 9446 CACUCCUCUAGUCUGGCCC 9447 GGGCCAGACUAGAGGAGUG 9448 AUUCUAGCACAUCUGGGCA 9449 UGCCCAGAUGUGCUAGAAU 9450 UUCUAGCACAUCUGGGCAA 9451 UUGCCCAGAUGUGCUAGAA 9452 UCUAGCACAUCUGGGCAAA 9453 UUUGCCCAGAUGUGCUAGA 9454 CUAGCACAUCUGGGCAAAA 9455 UUUUGCCCAGAUGUGCUAG 9456 GGGUGUAAAGGGACGUGCA 9457 UGCACGUCCCUUUACACCC 9458 GGUGUAAAGGGACGUGCAC 9459 GUGCACGUCCCUUUACACC 9460 GUGUAAAGGGACGUGCACA 9461 UGUGCACGUCCCUUUACAC 9462 UGUAAAGGGACGUGCACAG 9463 CUGUGCACGUCCCUUUACA 9464 GUAAAGGGACGUGCACAGA 9465 UCUGUGCACGUCCCUUUAC 9466 UAAAGGGACGUGCACAGAU 9467 AUCUGUGCACGUCCCUUUA 9468 AAAGGGACGUGCACAGAUC 9469 GAUCUGUGCACGUCCCUUU 9470 AAGGGACGUGCACAGAUCU 9471 AGAUCUGUGCACGUCCCUU 9472 AGGGACGUGCACAGAUCUA 9473 UAGAUCUGUGCACGUCCCU 9474 CGUGCACAGAUCUACUUAC 9475 GUAAGUAGAUCUGUGCACG 9476 GUGCACAGAUCUACUUACC 9477 GGUAAGUAGAUCUGUGCAC 9478 UGCACAGAUCUACUUACCA 9479 UGGUAAGUAGAUCUGUGCA 9480 GCACAGAUCUACUUACCAA 9481 UUGGUAAGUAGAUCUGUGC 9482 CACAGAUCUACUUACCAAG 9483 CUUGGUAAGUAGAUCUGUG 9484 ACAGAUCUACUUACCAAGC 9485 GCUUGGUAAGUAGAUCUGU 9486 CAGAUCUACUUACCAAGCU 9487 AGCUUGGUAAGUAGAUCUG 9488 AGAUCUACUUACCAAGCUG 9489 CAGCUUGGUAAGUAGAUCU 9490 AUCUACUUACCAAGCUGGG 9491 CCCAGCUUGGUAAGUAGAU 9492 UCUACUUACCAAGCUGGGA 9493 UCCCAGCUUGGUAAGUAGA 9494 CUUACCAAGCUGGGAGCAA 9495 UUGCUCCCAGCUUGGUAAG 9496 UUACCAAGCUGGGAGCAAG 9497 CUUGCUCCCAGCUUGGUAA 9498 UACCAAGCUGGGAGCAAGC 9499 GCUUGCUCCCAGCUUGGUA 9500 ACCAAGCUGGGAGCAAGCA 9501 UGCUUGCUCCCAGCUUGGU 9502 GCUGGGAGCAAGCAGGAUU 9503 AAUCCUGCUUGCUCCCAGC 9504 CUGGGAGCAAGCAGGAUUG 9505 CAAUCCUGCUUGCUCCCAG 9506 UGGGAGCAAGCAGGAUUGG 9507 CCAAUCCUGCUUGCUCCCA 9508 GGGAGCAAGCAGGAUUGGG 9509 CCCAAUCCUGCUUGCUCCC 9510 AAAGGUUAAGCAGCAGUAG 9511 CUACUGCUGCUUAACCUUU 9512 AAGGUUAAGCAGCAGUAGG 9513 CCUACUGCUGCUUAACCUU 9514 AGGUUAAGCAGCAGUAGGC 9515 GCCUACUGCUGCUUAACCU 9516 GGUGCCUACUCCUGUCCUG 9517 CAGGACAGGAGUAGGCACC 9518 GUGCCUACUCCUGUCCUGU 9519 ACAGGACAGGAGUAGGCAC 9520 UGCCUACUCCUGUCCUGUG 9521 CACAGGACAGGAGUAGGCA 9522 GCCUACUCCUGUCCUGUGC 9523 GCACAGGACAGGAGUAGGC 9524 CCUACUCCUGUCCUGUGCC 9525 GGCACAGGACAGGAGUAGG 9526 CUACUCCUGUCCUGUGCCU 9527 AGGCACAGGACAGGAGUAG 9528 UACUCCUGUCCUGUGCCUA 9529 UAGGCACAGGACAGGAGUA 9530 ACUCCUGUCCUGUGCCUAU 9531 AUAGGCACAGGACAGGAGU 9532 CUCCUGUCCUGUGCCUAUC 9533 GAUAGGCACAGGACAGGAG 9534 UCCUGUCCUGUGCCUAUCA 9535 UGAUAGGCACAGGACAGGA 9536 GUGCCUAUCACAUUUGCAG 9537 CUGCAAAUGUGAUAGGCAC 9538 CUAUCACAUUUGCAGAGGG 9539 CCCUCUGCAAAUGUGAUAG 9540 UAUCACAUUUGCAGAGGGU 9541 ACCCUCUGCAAAUGUGAUA 9542 AUCACAUUUGCAGAGGGUA 9543 UACCCUCUGCAAAUGUGAU 9544 UCACAUUUGCAGAGGGUAA 9545 UUACCCUCUGCAAAUGUGA 9546 CACAUUUGCAGAGGGUAAG 9547 CUUACCCUCUGCAAAUGUG 9548 ACAUUUGCAGAGGGUAAGA 9549 UCUUACCCUCUGCAAAUGU 9550

In some embodiments, the siRNA molecules targeted to Transcript E comprise or consist of the nucleotide sequences (sense and antisense strands) shown in Table 12.

TABLE 12 SEQ SEQ ID ID Sense Sequence NO: Antisense Sequence NO: GACCGCCUGCAGAAGGUUG 9551 CAACCUUCUGCAGGCGGUC 9552 ACCGCCUGCAGAAGGUUGA 9553 UCAACCUUCUGCAGGCGGU 9554 CCGCCUGCAGAAGGUUGAC 9555 GUCAACCUUCUGCAGGCGG 9556 CGCCUGCAGAAGGUUGACU 9557 AG UCAACCU UCUGCAGGCG 9558 GCCUGCAGAAGGUUGACUG 9559 CAGUCAACCUUCUGCAGGC 9560 CAGAAGGUUGACUGCGUGG 9561 CCACGCAGUCAACCUUCUG 9562 AGAAGGUUGACUGCGUGGU 9563 ACCACGCAGUCAACCUUCU 9564 GAAGGUUGACUGCGUGGUA 9565 UACCACGCAGUCAACCUUC 9566 AAGGUUGACUGCGUGGUAG 9567 CUACCACGCAGUCAACCUU 9568 AGGUUGACUGCGUGGUAGG 9569 CCUACCACGCAGUCAACCU 9570 GGUUGACUGCGUGGUAGGG 9571 CCCUACCACGCAGUCAACC 9572 CCAGAGCAAGCCGAAGGCA 9573 UGCCUUCGGCUUGCUCUGG 9574 CAGAGCAAGCCGAAGGCAA 9575 UUGCCUUCGGCUUGCUCUG 9576 AGAGCAAGCCGAAGGCAAG 9577 CUUGCCUUCGGCUUGCUCU 9578 GAGCAAGCCGAAGGCAAGC 9579 GCUUGCCUUCGGCUUGCUC 9580 AGCAAGCCGAAGGCAAGCA 9581 UGCUUGCCUUCGGCUUGCU 9582 GCAAGCCGAAGGCAAGCAC 9583 GUGCUUGCCUUCGGCUUGC 9584 CAAGCCGAAGGCAAGCACG 9585 CGUGCUUGCCUUCGGCUUG 9586 AAGCCGAAGGCAAGCACGA 9587 UCGUGCUUGCCUUCGGCUU 9588 AGCCGAAGGCAAGCACGAU 9589 AUCGUGCUUGCCUUCGGCU 9590 GCCGAAGGCAAGCACGAUG 9591 CAUCGUGCUUGCCUUCGGC 9592 AAGGCAAGCACGAUGGCGC 9593 GCGCCAUCGUGCUUGCCUU 9594 AGGCAAGCACGAUGGCGCU 9595 AGCGCCAUCGUGCUUGCCU 9596 AAGCACGAUGGCGCUCACC 9597 GGUGAGCGCCAUCGUGCUU 9598 AGCACGAUGGCGCUCACCA 9599 UGGUGAGCGCCAUCGUGCU 9600 CUGUAGCAGCCGAGCAUCA 9601 UGAUGCUCGGCUGCUACAG 9602 AGCCGAGCAUCAGCCCGAA 9603 UUCGGGCUGAUGCUCGGCU 9604 GUCAGAGUCUCCAGGCUCA 9605 UGAGCCUGGAGACUCUGAC 9606 UCAGAGUCUCCAGGCUCAG 9607 CUGAGCCUGGAGACUCUGA 9608 CAGAGUCUCCAGGCUCAGG 9609 CCUGAGCCUGGAGACUCUG 9610 AGAGUCUCCAGGCUCAGGU 9611 ACCUGAGCCUGGAGACUCU 9612 GAGUCUCCAGGCUCAGGUG 9613 CACCUGAGCCUGGAGACUC 9614 AGUCUCCAGGCUCAGGUGG 9615 CCACCUGAGCCUGGAGACU 9616 GGGUGGCACAGCUGGCAUA 9617 UAUGCCAGCUGUGCCACCC 9618 GUGGCACAGCUGGCAUACG 9619 CGUAUGCCAGCUGUGCCAC 9620 UGGCACAGCUGGCAUACGC 9621 GCGUAUGCCAGCUGUGCCA 9622 CUCCACAGGUGGCGGUAGA 9623 UCUACCGCCACCUGUGGAG 9624 UCCACAGGUGGCGGUAGAC 9625 GUCUACCGCCACCUGUGGA 9626 UGAGCAGCACGCUGGCGUA 9627 UACGCCAGCGUGCUGCUCA 9628 AGCAGCACGCUGGCGUACA 9629 UGUACGCCAGCGUGCUGCU 9630 GCAGCACGCUGGCGUACAU 9631 AUGUACGCCAGCGUGCUGC 9632 CAGCACGCUGGCGUACAUG 9633 CAUGUACGCCAGCGUGCUG 9634 AGCACGCUGGCGUACAUGC 9635 GCAUGUACGCCAGCGUGCU 9636 GCACGCUGGCGUACAUGCU 9637 AGCAUGUACGCCAGCGUGC 9638 CACGCUGGCGUACAUGCUG 9639 CAGCAUGUACGCCAGCGUG 9640 ACGCUGGCGUACAUGCUGA 9641 UCAGCAUGUACGCCAGCGU 9642 CUGGCGUACAUGCUGAGCG 9643 CGCUCAGCAUGUACGCCAG 9644 UGGCGUACAUGCUGAGCGC 9645 GCGCUCAGCAUGUACGCCA 9646 CGCGCACACGUAGUACACC 9647 GGUGUACUACGUGUGCGCG 9648 GCGCACACGUAGUACACCG 9649 CGGUGUACUACGUGUGCGC 9650 CGCACACGUAGUACACCGC 9651 GCGGUGUACUACGUGUGCG 9652 GCACACGUAGUACACCGCC 9653 GGCGGUGUACUACGUGUGC 9654 CACACGUAGUACACCGCCU 9655 AGGCGGUGUACUACGUGUG 9656 ACACGUAGUACACCGCCUU 9657 AAGGCGGUGUACUACGUGU 9658 CACGUAGUACACCGCCUUG 9659 CAAGGCGGUGUACUACGUG 9660 UAGUACACCGCCUUGCAGC 9661 GCUGCAAGGCGGUGUACUA 9662

In some embodiments, the siRNA molecules targeted to Transcript F comprise or consist of the nucleotide sequences (sense and antisense strands) shown in Table 13.

SEQ SEQ ID ID Sense Sequence NO: Antisense Sequence NO: AGUGGACAGUGAGGACUUC 9663 GAAGUCCUCACUGUCCACU 9664 GUGGACAGUGAGGACUUCU 9665 AGAAGUCCUCACUGUCCAC 9666 UGGACAGUGAGGACUUCUU 9667 AAGAAGUCCUCACUGUCCA 9668 GGACAGUGAGGACUUCUUC 9669 GAAGAAGUCCUCACUGUCC 9670 AGUGAGGACUUCUUCCAGC 9671 GCUGGAAGAAGUCCUCACU 9672 GUGAGGACUUCUUCCAGCU 9673 AGCUGGAAGAAGUCCUCAC 9674 UGAGGACUUCUUCCAGCUG 9675 CAGCUGGAAGAAGUCCUCA 9676 GAGGACUUCUUCCAGCUGC 9677 GCAGCUGGAAGAAGUCCUC 9678 GUGCCUGAUGGUGUUGCAG 9679 CUGCAACACCAUCAGGCAC 9680 GAUGGUGUUGCAGUCUGGU 9681 ACCAGACUGCAACACCAUC 9682 UGGUGUUGCAGUCUGGUCA 9683 UGACCAGACUGCAACACCA 9684 GGUGUUGCAGUCUGGUCAG 9685 CUGACCAGACUGCAACACC 9686 GUGUUGCAGUCUGGUCAGA 9687 UCUGACCAGACUGCAACAC 9688 UGCAGUCUGGUCAGAGCUG 9689 CAGCUCUGACCAGACUGCA 9690 GCAGUCUGGUCAGAGCUGG 9691 CCAGCUCUGACCAGACUGC 9692 CAGUCUGGUCAGAGCUGGA 9693 UCCAGCUCUGACCAGACUG 9694 AGUCUGGUCAGAGCUGGAG 9695 CUCCAGCUCUGACCAGACU 9696 GUCUGGUCAGAGCUGGAGC 9697 GCUCCAGCUCUGACCAGAC 9698 UCUGGUCAGAGCUGGAGCC 9699 GGCUCCAGCUCUGACCAGA 9700 UGGUCAGAGCUGGAGCCCU 9701 AGGGCUCCAGCUCUGACCA 9702 GGUCAGAGCUGGAGCCCUA 9703 UAGGGCUCCAGCUCUGACC 9704 GUCAGAGCUGGAGCCCUAC 9705 GUAGGGCUCCAGCUCUGAC 9706 CAAGGGUAAGAGGCCUAUA 9707 UAUAGGCCUCUUACCCUUG 9708 AAGGGUAAGAGGCCUAUAC 9709 GUAUAGGCCUCUUACCCUU 9710 AGGGUAAGAGGCCUAUACU 9711 AGUAUAGGCCUCUUACCCU 9712 GGGUAAGAGGCCUAUACUG 9713 CAGUAUAGGCCUCUUACCC 9714 GGUAAGAGGCCUAUACUGG 9715 CCAGUAUAGGCCUCUUACC 9716 GUAAGAGGCCUAUACUGGG 9717 CCCAGUAUAGGCCUCUUAC 9718 GGGCUGCUUCCAAUGCCUG 9719 CAGGCAUUGGAAGCAGCCC 9720 GGCUGCUUCCAAUGCCUGU 9721 ACAGGCAUUGGAAGCAGCC 9722 GCUGCUUCCAAUGCCUGUC 9723 GACAGGCAUUGGAAGCAGC 9724 CUGCUUCCAAUGCCUGUCC 9725 GGACAGGCAUUGGAAGCAG 9726 UGCUUCCAAUGCCUGUCCU 9727 AGGACAGGCAUUGGAAGCA 9728 GCUUCCAAUGCCUGUCCUU 9729 AAGGACAGGCAUUGGAAGC 9730 CUUCCAAUGCCUGUCCUUU 9731 AAAGGACAGGCAUUGGAAG 9732 UUCCAAUGCCUGUCCUUUA 9733 UAAAGGACAGGCAUUGGAA 9734 UCCAAUGCCUGUCCUUUAG 9735 CUAAAGGACAGGCAUUGGA 9736 CAAUGCCUGUCCUUUAGAG 9737 CUCUAAAGGACAGGCAUUG 9738 AAUGCCUGUCCUUUAGAGC 9739 GCUCUAAAGGACAGGCAUU 9740 AUGCCUGUCCUUUAGAGCU 9741 AGCUCUAAAGGACAGGCAU 9742 CUUCCUCUCUAGCUUAACC 9743 GGUUAAGCUAGAGAGGAAG 9744 UUCCUCUCUAGCUUAACCC 9745 GGGUUAAGCUAGAGAGGAA 9746 UCUCUAGCUUAACCCUGAU 9747 AUCAGGGUUAAGCUAGAGA 9748 UAGCUUAACCCUGAUCCUG 9749 CAGGAUCAGGGUUAAGCUA 9750 GACCAGGUGCAGGAGGAGU 9751 ACUCCUCCUGCACCUGGUC 9752 ACCAGGUGCAGGAGGAGUU 9753 AACUCCUCCUGCACCUGGU 9754 CCAGGUGCAGGAGGAGUUG 9755 CAACUCCUCCUGCACCUGG 9756 CAGGUGCAGGAGGAGUUGU 9757 ACAACUCCUCCUGCACCUG 9758 AGGUGCAGGAGGAGUUGUG 9759 CACAACUCCUCCUGCACCU 9760 UGCAGGAGGAGUUGUGGAA 9761 UUCCACAACUCCUCCUGCA 9762 GCAGGAGGAGUUGUGGAAU 9763 AUUCCACAACUCCUCCUGC 9764 AGGAGGAGUUGUGGAAUUG 9765 CAAUUCCACAACUCCUCCU 9766 GGAGGAGUUGUGGAAUUGU 9767 ACAAUUCCACAACUCCUCC 9768 GAGGAGUUGUGGAAUUGUC 9769 GACAAUUCCACAACUCCUC 9770 AGGAGUUGUGGAAUUGUCA 9771 UGACAAUUCCACAACUCCU 9772 GGAGUUGUGGAAUUGUCAA 9773 UUGACAAUUCCACAACUCC 9774 GAGUUGUGGAAUUGUCAAG 9775 CUUGACAAUUCCACAACUC 9776 AGUUGUGGAAUUGUCAAGG 9777 CCUUGACAAUUCCACAACU 9778 GUUGUGGAAUUGUCAAGGA 9779 UCCUUGACAAUUCCACAAC 9780 UGGAAUUGUCAAGGAUGUC 9781 GACAUCCUUGACAAUUCCA 9782 GGAAUUGUCAAGGAUGUCA 9783 UGACAUCCUUGACAAUUCC 9784 AGUCCAAGCGAGGGAGGGU 9785 ACCCUCCCUCGCUUGGACU 9786 CAAGCGAGGGAGGGUCUGA 9787 UCAGACCCUCCCUCGCUUG 9788 AAGCGAGGGAGGGUCUGAC 9789 GUCAGACCCUCCCUCGCUU 9790 CUGACCCAGUGCUGAUGGA 9791 UCCAUCAGCACUGGGUCAG 9792 AGAUUAGUGGUGGGUGUCU 9793 AGACACCCACCACUAAUCU 9794 AUUAGUGGUGGGUGUCUGG 9795 CCAGACACCCACCACUAAU 9796 UUAGUGGUGGGUGUCUGGU 9797 ACCAGACACCCACCACUAA 9798 UAGUGGUGGGUGUCUGGUA 9799 UACCAGACACCCACCACUA 9800 AGUGGUGGGUGUCUGGUAU 9801 AUACCAGACACCCACCACU 9802 GUGGUGGGUGUCUGGUAUG 9803 CAUACCAGACACCCACCAC 9804 UGGUGGGUGUCUGGUAUGA 9805 UCAUACCAGACACCCACCA 9806 GGUGGGUGUCUGGUAUGAG 9807 CUCAUACCAGACACCCACC 9808 GUGGGUGUCUGGUAUGAGG 9809 CCUCAUACCAGACACCCAC 9810 UGGGUGUCUGGUAUGAGGA 9811 UCCUCAUACCAGACACCCA 9812 GGGUGUCUGGUAUGAGGAU 9813 AUCCUCAUACCAGACACCC 9814 GGUGUCUGGUAUGAGGAUC 9815 GAUCCUCAUACCAGACACC 9816 GUGUCUGGUAUGAGGAUCU 9817 AGAUCCUCAUACCAGACAC 9818 UGUCUGGUAUGAGGAUCUA 9819 UAGAUCCUCAUACCAGACA 9820 CAAGGGUGUCCUACAGAGU 9821 ACUCUGUAGGACACCCUUG 9822 AAGGGUGUCCUACAGAGUG 9823 CACUCUGUAGGACACCCUU 9824 AGGGUGUCCUACAGAGUGG 9825 CCACUCUGUAGGACACCCU 9826 GGGUGUCCUACAGAGUGGA 9827 UCCACUCUGUAGGACACCC 9828 GGUGUCCUACAGAGUGGAG 9829 CUCCACUCUGUAGGACACC 9830 UCCUACAGAGUGGAGUGCU 9831 AGCACUCCACUCUGUAGGA 9832 AGUGGAGUGCUGUCAUAUG 9833 CAUAUGACAGCACUCCACU 9834 GUGGAGUGCUGUCAUAUGG 9835 CCAUAUGACAGCACUCCAC 9836 UGGAGUGCUGUCAUAUGGC 9837 GCCAUAUGACAGCACUCCA 9838 GGAGUGCUGUCAUAUGGCC 9839 GGCCAUAUGACAGCACUCC 9840 GAGUGCUGUCAUAUGGCCU 9841 AGGCCAUAUGACAGCACUC 9842 AGUGCUGUCAUAUGGCCUG 9843 CAGGCCAUAUGACAGCACU 9844 GUGCUGUCAUAUGGCCUGG 9845 CCAGGCCAUAUGACAGCAC 9846 UGCUGUCAUAUGGCCUGGG 9847 CCCAGGCCAUAUGACAGCA 9848 GCUGUCAUAUGGCCUGGGA 9849 UCCCAGGCCAUAUGACAGC 9850 CUGUCAUAUGGCCUGGGAC 9851 GUCCCAGGCCAUAUGACAG 9852 UGUCAUAUGGCCUGGGACG 9853 CGUCCCAGGCCAUAUGACA 9854 GUCAUAUGGCCUGGGACGG 9855 CCGUCCCAGGCCAUAUGAC 9856 AGAGGCCCAAGCACAGCAA 9857 UUGCUGUGCUUGGGCCUCU 9858 GAGGCCCAAGCACAGCAAG 9859 CUUGCUGUGCUUGGGCCUC 9860 AGGCCCAAGCACAGCAAGG 9861 CCUUGCUGUGCUUGGGCCU 9862 GGCCCAAGCACAGCAAGGA 9863 UCCUUGCUGUGCUUGGGCC 9864 CCAAGCACAGCAAGGACAU 9865 AUGUCCUUGCUGUGCUUGG 9866 GCCCGAUUCACCUUUGACG 9867 CGUCAAAGGUGAAUCGGGC 9868 GAUUCACCUUUGACGUGUA 9869 UACACGUCAAAGGUGAAUC 9870 AUUCACCUUUGACGUGUAC 9871 GUACACGUCAAAGGUGAAU 9872 UUGGCAGCCUGAAUGUCAA 9873 UUGACAUUCAGGCUGCCAA 9874 UGGCAGCCUGAAUGUCAAA 9875 UUUGACAUUCAGGCUGCCA 9876 GGCAGCCUGAAUGUCAAAG 9877 CUUUGACAUUCAGGCUGCC 9878 GCAGCCUGAAUGUCAAAGC 9879 GCUUUGACAUUCAGGCUGC 9880 CAGCCUGAAUGUCAAAGCC 9881 GGCUUUGACAUUCAGGCUG 9882 AGCCUGAAUGUCAAAGCCA 9883 UGGCUUUGACAUUCAGGCU 9884 GCCUGAAUGUCAAAGCCAC 9885 GUGGCUUUGACAUUCAGGC 9886 GUCAAAGCCACAUUCUACG 9887 CGUAGAAUGUGGCUUUGAC 9888 UCAAAGCCACAUUCUACGG 9889 CCGUAGAAUGUGGCUUUGA 9890 CAAAGCCACAUUCUACGGG 9891 CCCGUAGAAUGUGGCUUUG 9892 AAAGCCACAUUCUACGGGC 9893 GCCCGUAGAAUGUGGCUUU 9894 GCCACAUUCUACGGGCUCU 9895 AGAGCCCGUAGAAUGUGGC 9896 CCACAUUCUACGGGCUCUA 9897 UAGAGCCCGUAGAAUGUGG 9898 CACAUUCUACGGGCUCUAC 9899 GUAGAGCCCGUAGAAUGUG 9900 UUCUACGGGCUCUACUCUA 9901 UAGAGUAGAGCCCGUAGAA 9902 UCUACGGGCUCUACUCUAU 9903 AUAGAGUAGAGCCCGUAGA 9904 CUACGGGCUCUACUCUAUG 9905 CAUAGAGUAGAGCCCGUAG 9906 CUCUAUGAGUUGUGACUUU 9907 AAAGUCACAACUCAUAGAG 9908 UCUAUGAGUUGUGACUUUC 9909 GAAAGUCACAACUCAUAGA 9910 UGAGUUGUGACUUUCAAGG 9911 CCUUGAAAGUCACAACUCA 9912 GAGUUGUGACUUUCAAGGA 9913 UCCUUGAAAGUCACAACUC 9914 AGUUGUGACUUUCAAGGAC 9915 GUCCUUGAAAGUCACAACU 9916 GUUGUGACUUUCAAGGACU 9917 AGUCCUUGAAAGUCACAAC 9918 GACUUUCAAGGACUUGGCC 9919 GGCCAAGUCCUUGAAAGUC 9920 UUUCAAGGACUUGGCCCAA 9921 UUGGGCCAAGUCCUUGAAA 9922 UUCAAGGACUUGGCCCAAA 9923 UUUGGGCCAAGUCCUUGAA 9924 CCCUACAGUUGGAUAGUCC 9925 GGACUAUCCAACUGUAGGG 9926 CCUACAGUUGGAUAGUCCC 9927 GGGACUAUCCAACUGUAGG 9928 AUUCGUCCUCUUGCACCCA 9929 UGGGUGCAAGAGGACGAAU 9930 UUCGUCCUCUUGCACCCAC 9931 GUGGGUGCAAGAGGACGAA 9932 UCCUCUUGCACCCACCUAC 9933 GUAGGUGGGUGCAAGAGGA 9934 CCUCUUGCACCCACCUACC 9935 GGUAGGUGGGUGCAAGAGG 9936 CUCUUGCACCCACCUACCC 9937 GGGUAGGUGGGUGCAAGAG 9938 CUAGUUAGCUCUUGCUUGU 9939 ACAAGCAAGAGCUAACUAG 9940 UAGUUAGCUCUUGCUUGUG 9941 CACAAGCAAGAGCUAACUA 9942 AGUUAGCUCUUGCUUGUGG 9943 CCACAAGCAAGAGCUAACU 9944 UUAGCUCUUGCUUGUGGAA 9945 UUCCACAAGCAAGAGCUAA 9946 UCCUCAUCUCCCAGCUUGA 9947 UCAAGCUGGGAGAUGAGGA 9948 AUCUCCCAGCUUGAUGGCU 9949 AGCCAUCAAGCUGGGAGAU 9950 UCUCCCAGCUUGAUGGCUU 9951 AAGCCAUCAAGCUGGGAGA 9952 CUCCCAGCUUGAUGGCUUC 9953 GAAGCCAUCAAGCUGGGAG 9954 UCCCAGCUUGAUGGCUUCC 9955 GGAAGCCAUCAAGCUGGGA 9956 CCCAGCUUGAUGGCUUCCU 9957 AGGAAGCCAUCAAGCUGGG 9958 CCAGCUUGAUGGCUUCCUC 9959 GAGGAAGCCAUCAAGCUGG 9960 UGAUGGCUUCCUCCCAAGU 9961 ACUUGGGAGGAAGCCAUCA 9962 GAUGGCUUCCUCCCAAGUU 9963 AACUUGGGAGGAAGCCAUC 9964 GGCUUCCUCCCAAGUUUUC 9965 GAAAACUUGGGAGGAAGCC 9966 CCUCCCAAGUUUUCCAAAU 9967 AUUUGGAAAACUUGGGAGG 9968 CCCAAGUUUUCCAAAUCAU 9969 AUGAUUUGGAAAACUUGGG 9970 CCAAGUUUUCCAAAUCAUC 9971 GAUGAUUUGGAAAACUUGG 9972 CAAGUUUUCCAAAUCAUCU 9973 AGAUGAUUUGGAAAACUUG 9974 AAGUUUUCCAAAUCAUCUG 9975 CAGAUGAUUUGGAAAACUU 9976 GUUUUCCAAAUCAUCUGAU 9977 AUCAGAUGAUUUGGAAAAC 9978 AUCUGAUUUCCUCUUGUCU 9979 AGACAAGAGGAAAUCAGAU 9980 UCUGAUUUCCUCUUGUCUC 9981 GAGACAAGAGGAAAUCAGA 9982 CUGAUUUCCUCUUGUCUCU 9983 AGAGACAAGAGGAAAUCAG 9984 CUCUUGUCUCUGCCAUUCA 9985 UGAAUGGCAGAGACAAGAG 9986 GUUGGACCUCCACACUGCU 9987 AGCAGUGUGGAGGUCCAAC 9988 CCACACUGCUGCAAGGCCU 9989 AGGCCUUGCAGCAGUGUGG 9990 CACACUGCUGCAAGGCCUG 9991 CAGGCCUUGCAGCAGUGUG 9992 ACACUGCUGCAAGGCCUGG 9993 CCAGGCCUUGCAGCAGUGU 9994 UGCAAGGCCUGGGCCAUAU 9995 AUAUGGCCCAGGCCUUGCA 9996 GCAAGGCCUGGGCCAUAUG 9997 CAUAUGGCCCAGGCCUUGC 9998 CAAGGCCUGGGCCAUAUGU 9999 ACAUAUGGCCCAGGCCUUG 10000 AAGGCCUGGGCCAUAUGUU 10001 AACAUAUGGCCCAGGCCUU 10002 AGGCCUGGGCCAUAUGUUG 10003 CAACAUAUGGCCCAGGCCU 10004 GGCCUGGGCCAUAUGUUGC 10005 GCAACAUAUGGCCCAGGCC 10006 GCCUGGGCCAUAUGUUGCU 10007 AGCAACAUAUGGCCCAGGC 10008 CCUGGGCCAUAUGUUGCUG 10009 CAGCAACAUAUGGCCCAGG 10010 GGCCAUAUGUUGCUGGGAA 10011 UUCCCAGCAACAUAUGGCC 10012 CCAUAUGUUGCUGGGAAUU 10013 AAUUCCCAGCAACAUAUGG 10014 GGAAUUUCCUCCACCCUUC 10015 GAAGGGUGGAGGAAAUUCC 10016 GAAUUUCCUCCACCCUUCG 10017 CGAAGGGUGGAGGAAAUUC 10018 AAUUUCCUCCACCCUUCGU 10019 ACGAAGGGUGGAGGAAAUU 10020 AUUUCCUCCACCCUUCGUC 10021 GACGAAGGGUGGAGGAAAU 10022 UUUCCUCCACCCUUCGUCA 10023 UGACGAAGGGUGGAGGAAA 10024 UUCCUCCACCCUUCGUCAU 10025 AUGACGAAGGGUGGAGGAA 10026 UCCUCCACCCUUCGUCAUG 10027 CAUGACGAAGGGUGGAGGA 10028 CCUCCACCCUUCGUCAUGC 10029 GCAUGACGAAGGGUGGAGG 10030 CUCCACCCUUCGUCAUGCA 10031 UGCAUGACGAAGGGUGGAG 10032 CCUUCGUCAUGCAGUGGAG 10033 CUCCACUGCAUGACGAAGG 10034 CUUCGUCAUGCAGUGGAGG 10035 CCUCCACUGCAUGACGAAG 10036 UUCGUCAUGCAGUGGAGGG 10037 CCCUCCACUGCAUGACGAA 10038 CGCCUCCAUUCCUACUAAG 10039 CUUAGUAGGAAUGGAGGCG 10040 GCCUCCAUUCCUACUAAGG 10041 CCUUAGUAGGAAUGGAGGC 10042 CCUCCAUUCCUACUAAGGG 10043 CCCUUAGUAGGAAUGGAGG 10044

In some embodiments, the PNPLA3 inhibitor comprises an inhibitory nucleic acid molecule. Examples of inhibitory nucleic acid molecules include, but are not limited to, antisense nucleic acid molecules, siRNAs, and shRNAs. Such inhibitory nucleic acid molecules can be designed to target any region of a PNPLA3 mRNA. In some embodiments, the antisense RNA, siRNA, or shRNA hybridizes to a sequence within a PNPLA3 genomic nucleic acid molecule or mRNA molecule and decreases expression of the PNPLA3 polypeptide in a cell in the subject. In some embodiments, the PNPLA3 inhibitor comprises an antisense RNA that hybridizes to a PNPLA3 genomic nucleic acid molecule or mRNA molecule and decreases expression of the PNPLA3 polypeptide in a cell in the subject. In some embodiments, the PNPLA3 inhibitor comprises an siRNA that hybridizes to a PNPLA3 genomic nucleic acid molecule or mRNA molecule and decreases expression of the PNPLA3 polypeptide in a cell in the subject. In some embodiments, the PNPLA3 inhibitor comprises an shRNA that hybridizes to a PNPLA3 genomic nucleic acid molecule or mRNA molecule and decreases expression of the PNPLA3 polypeptide in a cell in the subject.

The inhibitory nucleic acid molecules described herein can be targeted to various PNPLA3 transcripts. For example, the inhibitory nucleic acid molecules described herein can be targeted to the PNPLA3 transcripts (derived from chromosome 22; Ensembl Gene ID=ENSG00000100344.11; hgnc symbol=PNPLA3).

In some embodiments, the HSD17B13 inhibitor comprises an inhibitory nucleic acid molecule. Examples of inhibitory nucleic acid molecules include, but are not limited to, antisense nucleic acid molecules, siRNAs, and shRNAs. Such inhibitory nucleic acid molecules can be designed to target any region of a HSD17B13 mRNA. In some embodiments, the antisense RNA, siRNA, or shRNA hybridizes to a sequence within a HSD17B13 genomic nucleic acid molecule or mRNA molecule and decreases expression of the HSD17B13 polypeptide in a cell in the subject. In some embodiments, the HSD17B13 inhibitor comprises an antisense RNA that hybridizes to a HSD17B13 genomic nucleic acid molecule or mRNA molecule and decreases expression of the HSD17B13 polypeptide in a cell in the subject. In some embodiments, the HSD17B13 inhibitor comprises an siRNA that hybridizes to a HSD17B13 genomic nucleic acid molecule or mRNA molecule and decreases expression of the HSD17B13 polypeptide in a cell in the subject. In some embodiments, the HSD17B13 inhibitor comprises an shRNA that hybridizes to a HSD17B13 genomic nucleic acid molecule or mRNA molecule and decreases expression of the HSD17B13 polypeptide in a cell in the subject.

The inhibitory nucleic acid molecules described herein can be targeted to various HSD17B13 transcripts. For example, the inhibitory nucleic acid molecules described herein can be targeted to the HSD17B13 transcripts (derived from chromosome 4; Ensembl Gene ID=ENSG00000170509.8; hgnc symbol=HSD17B13).

The inhibitory nucleic acid molecules disclosed herein can comprise RNA, DNA, or both RNA and DNA. The inhibitory nucleic acid molecules can also be linked or fused to a heterologous nucleic acid sequence, such as in a vector, or a heterologous label. For example, the inhibitory nucleic acid molecules disclosed herein can be within a vector or as an exogenous donor sequence comprising the inhibitory nucleic acid molecule and a heterologous nucleic acid sequence. The inhibitory nucleic acid molecules can also be linked or fused to a heterologous label. The label can be directly detectable (such as, for example, fluorophore) or indirectly detectable (such as, for example, hapten, enzyme, or fluorophore quencher). Such labels can be detectable by spectroscopic, photochemical, biochemical, immunochemical, or chemical means. Such labels include, for example, radiolabels, pigments, dyes, chromogens, spin labels, and fluorescent labels. The label can also be, for example, a chemiluminescent substance; a metal-containing substance; or an enzyme, where there occurs an enzyme-dependent secondary generation of signal. The term “label” can also refer to a “tag” or hapten that can bind selectively to a conjugated molecule such that the conjugated molecule, when added subsequently along with a substrate, is used to generate a detectable signal. For example, biotin can be used as a tag along with an avidin or streptavidin conjugate of horseradish peroxidate (HRP) to bind to the tag, and examined using a calorimetric substrate (such as, for example, tetramethylbenzidine (TMB)) or a fluorogenic substrate to detect the presence of HRP. Exemplary labels that can be used as tags to facilitate purification include, but are not limited to, myc, HA, FLAG or 3×FLAG, 6×His (SEQ ID NO:10045) or polyhistidine, glutathione-S-transferase (GST), maltose binding protein, an epitope tag, or the Fc portion of immunoglobulin. Numerous labels include, for example, particles, fluorophores, haptens, enzymes and their calorimetric, fluorogenic and chemiluminescent substrates and other labels.

The inhibitory nucleic acid molecules disclosed herein can comprise, for example, nucleotides or non-natural or modified nucleotides, such as nucleotide analogs or nucleotide substitutes. Such nucleotides include a nucleotide that contains a modified base, sugar, or phosphate group, or that incorporates a non-natural moiety in its structure. Examples of non-natural nucleotides include, but are not limited to, dideoxynucleotides, biotinylated, aminated, deaminated, alkylated, benzylated, and fluorophor-labeled nucleotides.

The inhibitory nucleic acid molecules disclosed herein can also comprise one or more nucleotide analogs or substitutions. A nucleotide analog is a nucleotide which contains a modification to either the base, sugar, or phosphate moieties. Modifications to the base moiety include, but are not limited to, natural and synthetic modifications of A, C, G, and T/U, as well as different purine or pyrimidine bases such as, for example, pseudouridine, uracil-5-yl, hypoxanthin-9-yl (I), and 2-aminoadenin-9-yl. Modified bases include, but are not limited to, 5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo (such as, for example, 5-bromo), 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine, 7-methyladenine, 8-azaguanine, 8-azaadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, and 3-deazaadenine.

Nucleotide analogs can also include modifications of the sugar moiety. Modifications to the sugar moiety include, but are not limited to, natural modifications of the ribose and deoxy ribose as well as synthetic modifications. Sugar modifications include, but are not limited to, the following modifications at the 2′ position: OH; F; O-, S-, or N-alkyl; O-, S-, or N-alkenyl; O-, S- or N-alkynyl; or O-alkyl-O-alkyl, wherein the alkyl, alkenyl, and alkynyl may be substituted or unsubstituted C₁₋₁₀alkyl or C₂₋₁₀alkenyl, and C₂₋₁₀alkynyl. Exemplary 2′ sugar modifications also include, but are not limited to, —O[(CH₂)_(n)O]_(m)CH₃, —O(CH₂)_(n)OCH₃, —O(CH₂)_(n)NH₂, —O(CH₂)_(n)CH₃, —O(CH₂)_(n)—ONH₂, and —O(CH₂)_(n)ON[(CH₂)_(n)CH₃)]₂, where n and m, independently, are from 1 to about 10. Other modifications at the 2′ position include, but are not limited to, C₁₋₁₀alkyl, substituted lower alkyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH₃, OCN, Cl, Br, CN, CF₃, OCF₃, SOCH₃, SO₂CH₃, ONO₂, NO₂, N₃, NH₂, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleaving group, a reporter group, an intercalator, a group for improving the pharmacokinetic properties of an oligonucleotide, or a group for improving the pharmacodynamic properties of an oligonucleotide, and other substituents having similar properties. Similar modifications may also be made at other positions on the sugar, particularly the 3′ position of the sugar on the 3′ terminal nucleotide or in 2′-5′ linked oligonucleotides and the 5′ position of 5′ terminal nucleotide. Modified sugars can also include those that contain modifications at the bridging ring oxygen, such as CH₂ and S. Nucleotide sugar analogs can also have sugar mimetics, such as cyclobutyl moieties in place of the pentofuranosyl sugar.

Nucleotide analogs can also be modified at the phosphate moiety. Modified phosphate moieties include, but are not limited to, those that can be modified so that the linkage between two nucleotides contains a phosphorothioate, chiral phosphorothioate, phosphorodithioate, phosphotriester, aminoalkylphosphotriester, methyl and other alkyl phosphonates including 3′-alkylene phosphonate and chiral phosphonates, phosphinates, phosphoramidates including 3′-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, and boranophosphates. These phosphate or modified phosphate linkage between two nucleotides can be through a 3′-5′ linkage or a 2′-5′ linkage, and the linkage can contain inverted polarity such as 3′-5′ to 5′-3′ or 2′-5′ to 5′-2′. Various salts, mixed salts, and free acid forms are also included. Nucleotide substitutes also include peptide nucleic acids (PNAs).

In some embodiments, the antisense nucleic acid molecules are gapmers, whereby the first one to seven nucleotides at the 5′ and 3′ ends each have 2′-methoxyethyl (2′-MOE) modifications. In some embodiments, the first five nucleotides at the 5′ and 3′ ends each have 2′-MOE modifications. In some embodiments, the first one to seven nucleotides at the 5′ and 3′ ends are RNA nucleotides. In some embodiments, the first five nucleotides at the 5′ and 3′ ends are RNA nucleotides. In some embodiments, each of the backbone linkages between the nucleotides is a phosphorothioate linkage.

In some embodiments, the siRNA molecules have termini modifications. In some embodiments, the 5′ end of the antisense strand is phosphorylated. In some embodiments, 5′-phosphate analogs that cannot be hydrolyzed, such as 5′-(E)-vinyl-phosphonate are used.

In some embodiments, the siRNA molecules have backbone modifications. In some embodiments, the modified phosphodiester groups that link consecutive ribose nucleosides have been shown to enhance the stability and in vivo bioavailability of siRNAs The non-ester groups (—OH, ═O) of the phosphodiester linkage can be replaced with sulfur, boron, or acetate to give phosphorothioate, boranophosphate, and phosphonoacetate linkages. In addition, substituting the phosphodiester group with a phosphotriester can facilitate cellular uptake of siRNAs and retention on serum components by eliminating their negative charge. In some embodiments, the siRNA molecules have sugar modifications. In some embodiments, the sugars are deprotonated (reaction catalyzed by exo- and endonucleases) whereby the 2′-hydroxyl can act as a nucleophile and attack the adjacent phosphorous in the phosphodiester bond. Such alternatives include 2′-O-methyl, 2′-O-methoxyethyl, and 2′-fluoro modifications.

In some embodiments, the siRNA molecules have base modifications. In some embodiments, the bases can be substituted with modified bases such as pseudouridine, 5′-methylcytidine, N6-methyladenosine, inosine, and N7-methylguanosine.

In some embodiments, the siRNA molecules are conjugated to lipids. Lipids can be conjugated to the 5′ or 3′ termini of siRNA to improve their in vivo bioavailability by allowing them to associate with serum lipoproteins. Representative lipids include, but are not limited to, cholesterol and vitamin E, and fatty acids, such as palmitate and tocopherol.

In some embodiments, a representative siRNA has the following formula:

Sense: mN*mN*/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/*mN*/32FN/

Antisense: /52FN/*/i2FN/*mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN/i2FN/mN*N*N

wherein: “N” is the base; “2F” is a 2′-F modification; “m” is a 2′-O-methyl modification, “I” is an internal base; and “*” is a phosphorothioate backbone linkage.

The present disclosure also provides vectors comprising any one or more of the inhibitory nucleic acid molecules disclosed herein. In some embodiments, the vectors comprise any one or more of the inhibitory nucleic acid molecules disclosed herein and a heterologous nucleic acid. The vectors can be viral or nonviral vectors capable of transporting a nucleic acid molecule. In some embodiments, the vector is a plasmid or cosmid (such as, for example, a circular double-stranded DNA into which additional DNA segments can be ligated). In some embodiments, the vector is a viral vector, wherein additional DNA segments can be ligated into the viral genome. Expression vectors include, but are not limited to, plasmids, cosmids, retroviruses, adenoviruses, adeno-associated viruses (AAV), plant viruses such as cauliflower mosaic virus and tobacco mosaic virus, yeast artificial chromosomes (YACs), Epstein-Barr (EBV)-derived episomes, and other expression vectors known in the art.

The present disclosure also provides compositions comprising any one or more of the inhibitory nucleic acid molecules disclosed herein. In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the compositions comprise a carrier and/or excipient. Examples of carriers include, but are not limited to, poly(lactic acid) (PLA) microspheres, poly(D,L-lactic-coglycolic-acid) (PLGA) microspheres, liposomes, micelles, inverse micelles, lipid cochleates, and lipid microtubules. A carrier may comprise a buffered salt solution such as PBS, HBSS, etc.

In some embodiments, the CIDEB inhibitor comprises a nuclease agent that induces one or more nicks or double-strand breaks at a recognition sequence(s) or a DNA-binding protein that binds to a recognition sequence within a CIDEB genomic nucleic acid molecule. The recognition sequence can be located within a coding region of the CIDEB gene, or within regulatory regions that influence the expression of the gene. A recognition sequence of the DNA-binding protein or nuclease agent can be located in an intron, an exon, a promoter, an enhancer, a regulatory region, or any non-protein coding region. The recognition sequence can include or be proximate to the start codon of the CIDEB gene. For example, the recognition sequence can be located about 10, about 20, about 30, about 40, about 50, about 100, about 200, about 300, about 400, about 500, or about 1,000 nucleotides from the start codon.

In some embodiments, the PNPLA3 inhibitor comprises a nuclease agent that induces one or more nicks or double-strand breaks at a recognition sequence(s) or a DNA-binding protein that binds to a recognition sequence within a PNPLA3 genomic nucleic acid molecule. The recognition sequence can be located within a coding region of the PNPLA3 gene, or within regulatory regions that influence the expression of the gene. A recognition sequence of the DNA-binding protein or nuclease agent can be located in an intron, an exon, a promoter, an enhancer, a regulatory region, or any non-protein coding region. The recognition sequence can include or be proximate to the start codon of the PNPLA3 gene. For example, the recognition sequence can be located about 10, about 20, about 30, about 40, about 50, about 100, about 200, about 300, about 400, about 500, or about 1,000 nucleotides from the start codon.

In some embodiments, the HSD17B13 inhibitor comprises a nuclease agent that induces one or more nicks or double-strand breaks at a recognition sequence(s) or a DNA-binding protein that binds to a recognition sequence within an HSD17B13 genomic nucleic acid molecule. The recognition sequence can be located within a coding region of the HSD17B13 gene, or within regulatory regions that influence the expression of the gene. A recognition sequence of the DNA-binding protein or nuclease agent can be located in an intron, an exon, a promoter, an enhancer, a regulatory region, or any non-protein coding region. The recognition sequence can include or be proximate to the start codon of the HSD17B13 gene. For example, the recognition sequence can be located about 10, about 20, about 30, about 40, about 50, about 100, about 200, about 300, about 400, about 500, or about 1,000 nucleotides from the start codon.

As another example, two or more nuclease agents can be used, each targeting a nuclease recognition sequence including or proximate to the start codon. As another example, two nuclease agents can be used, one targeting a nuclease recognition sequence including or proximate to the start codon, and one targeting a nuclease recognition sequence including or proximate to the stop codon, wherein cleavage by the nuclease agents can result in deletion of the coding region between the two nuclease recognition sequences. Any nuclease agent that induces a nick or double-strand break into a desired recognition sequence can be used in the methods and compositions disclosed herein. Any DNA-binding protein that binds to a desired recognition sequence can be used in the methods and compositions disclosed herein.

Suitable nuclease agents and DNA-binding proteins for use herein include, but are not limited to, zinc finger protein or zinc finger nuclease (ZFN) pair, Transcription Activator-Like Effector (TALE) protein or Transcription Activator-Like Effector Nuclease (TALEN), or Clustered Regularly Interspersed Short Palindromic Repeats (CRISPR)/CRISPR-associated (Cas) systems. The length of the recognition sequence can vary, and includes, for example, recognition sequences that are about 30-36 bp for a zinc finger protein or ZFN pair, about 15-18 bp for each ZFN, about 36 bp for a TALE protein or TALEN, and about 20 bp for a CRISPR/Cas guide RNA.

In some embodiments, CRISPR/Cas systems can be used to modify a CIDEB genomic nucleic acid molecule, a PNPLA3 genomic nucleic acid molecule, or an HSD17B13 genomic nucleic acid molecule within a cell. The methods and compositions disclosed herein can employ CRISPR-Cas systems by utilizing CRISPR complexes (comprising a guide RNA (gRNA) complexed with a Cas protein) for site-directed cleavage of CIDEB nucleic acid molecules, PNPLA3 nucleic acid molecules, or HSD17B13 nucleic acid molecules.

Cas proteins generally comprise at least one RNA recognition or binding domain that can interact with gRNAs. Cas proteins can also comprise nuclease domains (such as, for example, DNase or RNase domains), DNA binding domains, helicase domains, protein-protein interaction domains, dimerization domains, and other domains. Suitable Cas proteins include, for example, a wild type Cas9 protein and a wild type Cpf1 protein (such as, for example, FnCpf1). A Cas protein can have full cleavage activity to create a double-strand break in a CIDEB genomic nucleic acid molecule, a PNPLA3 genomic nucleic acid molecule, or an HSD17B13 genomic nucleic acid molecule, or it can be a nickase that creates a single-strand break in a CIDEB genomic nucleic acid molecule, a PNPLA3 genomic nucleic acid molecule, or an HSD17B13 genomic nucleic acid molecule. Additional examples of Cas proteins include, but are not limited to, Cas1, Cas1B, Cast, Cas3, Cas4, Cas5, Cas5e (CasD), Cas6, Cas6e, Cas6f, Cas7, Cas8a1, Cas8a2, Cas8b, Cas8c, Cas9 (Csn1 or Csx12), Cas10, Cas10d, Cas12a, CasF, CasG, CasH, Csy1, Csy2, Csy3, Cse1 (CasA), Cse2 (CasB), Cse3 (CasE), Cse4 (CasC), Csc1, Csc2, Csa5, Csn2, Csm2, Csm3, Csm4, Csm5, Csm6, Cmr1, Cmr3, Cmr4, Cmr5, Cmr6, Csb1, Csb2, Csb3, Csx17, Csx14, Csx10, Csx16, CsaX, Csx3, Csx1, Csx15, Csf1, Csf2, Csf3, Csf4, and Cu1966, and homologs or modified versions thereof. In some embodiments, a Cas system, such as Cas12a, can have multiple gRNAs encoded into a single crRNA. Cas proteins can also be operably linked to heterologous polypeptides as fusion proteins. For example, a Cas protein can be fused to a cleavage domain, an epigenetic modification domain, a transcriptional activation domain, or a transcriptional repressor domain. Cas proteins can be provided in any form. For example, a Cas protein can be provided in the form of a protein, such as a Cas protein complexed with a gRNA. Alternately, a Cas protein can be provided in the form of a nucleic acid molecule encoding the Cas protein, such as an RNA or DNA.

In some embodiments, targeted genetic modifications of CIDEB genomic nucleic acid molecules can be generated by contacting a cell with a Cas protein and one or more gRNAs that hybridize to one or more gRNA recognition sequences within a target genomic locus in the CIDEB genomic nucleic acid molecule. For example, a gRNA recognition sequence can be located within a region of SEQ ID NO:1. For example, the gRNA recognition sequence can be located from about 1000, from about 500, from about 400, from about 300, from about 200, from about 100, from about 50, from about 45, from about 40, from about 35, from about 30, from about 25, from about 20, from about 15, from about 10, or from about 5 nucleotides of a position corresponding to any one or more of positions: 14:24305635, 14:24305641, 14:24305650, 14:24305657, 14:24305662, 14:24305667, 14:24305671, 14:24305701, 14:24305709, 14:24305718, 14:24305721, 14:24305728, 14:24305743, 14:24305948, 14:24305966, 14:24305974, 14:24305980, 14:24305988, 14:24306014, 14:24306034, 14:24306041, 14:24306044, 14:24306047, 14:24306051, 14:24306064, 14:24306074, 14:24306077, 14:24306082, 14:24306083, 14:24306095, 14:24306122, 14:24306134, 14:24306373, 14:24306379, 14:24306382, 14:24306383, 14:24306426, 14:24306437, 14:24306439, 14:24306442, 14:24306444, 14:24306457, 14:24306463, 14:24306469, 14:24306480, 14:24306486, 14:24306504, 14:24306519, 14:24307382, 14:24307405, 14:24307417, 14:24307421, 14:24307441, 14:24307444, 14:24307444, 14:24307450, 14:24307461, 14:24307469, 14:24307474, 14:24307475, 14:24307833, 14:24307851, 14:24306426, 14:24307849, 14:24307448, 14:24305671, 14:24305663, 14:24305686, 14:24307829, 14:24307818, 14:24307856, 14:24306423, 14:24306061, 14:24307390, 14:24306382, 14:24306373, 14:24305733, 14:24307858, 14:24306387, 14:24305637, 14:24306062, 14:24307853, 14:24307450, 14:24306052, 14:24305673, 14:24306043, 14:24307834, 14:24306417, 14:24307451, 14:24307436, 14:24305953, 14:24306489, 14:24307441, 14:24306375, 14:24305657, 14:24306427, 14:24306524, 14:24307516, 14:24307840, 14:24307501, 14:24305968, 14:24305986, 14:24307441, 14:24307459, 14:24306017, 14:24307424, 14:24306072, 14:24307423, 14:24307450, 14:24306420, 14:24307454, 14:24305653, 14:24307442, 14:24306002, 14:24306076, 14:24305664, 14:24305961, 14:24305706, 14:24305946, 14:24306455, 14:24307468, 14:24307825, 14:24306110, 14:24305710, 14:24307483, 14:24306459, 14:24305754, 14:24305650, 14:24305691, 14:24306508, 14:24306039, 14:24306139, 14:24306391, 14:24306373, 14:24307498, 14:24307415, 14:24306138, 14:24307453, 14:24305692, 14:24305683, 14:24307484, 14:24307385, 14:24306519, 14:24307839, 14:24305965, 14:24305988, 14:24306087, 14:24307439, 14:24307477, 14:24306436, 14:24306507, 14:24307397, 14:24307495, 14:24306034, 14:24306013, 14:24307381, 14:24306383, 14:24305638, 14:24307420, 14:24306020, 14:24306470, 14:24307435, 14:24306469, 14:24306451, 14:24306403, 14:24307515, 14:24307489, 14:24307414, 14:24306483, 14:24305755, 14:24305766, 14:24306064, 14:24307516, 14:24305766, 14:24306489, 14:24306097, 14:24305763, 14:24307447, 14:24307402, 14:24305972, 14:24306423, 14:24305974, 14:24307411, 14:24306121, 14:24307516, 14:24306424, 14:24306039, 14:24307853, 14:24306388, 14:24305990, 14:24307822, 14:24305640, 14:24307418, 14:24305758, 14:24306131, 14:24305953, 14:24305730, 14:24306418, 14:24306059, 14:24307842, 14:24307837, 14:24306095, 14:24306109, 14:24307822, 14:24306077, 14:24307824, 14:24306080, 14:24305649, 14:24306433, 14:24306420, 14:24305658, 14:24306472, 14:24307412, 14:24306062, 14:24306044, 14:24306047, 14:24306126, 14:24306449, 14:24307391, or 14:24307857 (according to GRCh38/hg38 human genome assembly coordinates). The gRNA recognition sequence can include or be proximate to the start codon of a CIDEB genomic nucleic acid molecule or the stop codon of a CIDEB genomic nucleic acid molecule. For example, the gRNA recognition sequence can be located from about 10, from about 20, from about 30, from about 40, from about 50, from about 100, from about 200, from about 300, from about 400, from about 500, or from about 1,000 nucleotides of the start codon or the stop codon.

The gRNA recognition sequences within a target genomic locus in a CIDEB genomic nucleic acid molecule can be located near a Protospacer Adjacent Motif (PAM) sequence, which is a 2-6 base pair DNA sequence immediately following the DNA sequence targeted by the Cas9 nuclease. The canonical PAM is the sequence 5′-NGG-3′ where “N” is any nucleobase followed by two guanine (“G”) nucleobases. gRNAs can transport Cas9 to anywhere in the genome for gene editing, but no editing can occur at any site other than one at which Cas9 recognizes PAM. In addition, 5′-NGA-3′ can be a highly efficient non-canonical PAM for human cells. Generally, the PAM is about 2-6 nucleotides downstream of the DNA sequence targeted by the gRNA. The PAM can flank the gRNA recognition sequence. In some embodiments, the gRNA recognition sequence can be flanked on the 3′ end by the PAM. In some embodiments, the gRNA recognition sequence can be flanked on the 5′ end by the PAM. For example, the cleavage site of Cas proteins can be about 1 to about 10, about 2 to about 5 base pairs, or three base pairs upstream or downstream of the PAM sequence. In some embodiments (such as when Cas9 from S. pyogenes or a closely related Cas9 is used), the PAM sequence of the non-complementary strand can be 5′-NGG-3′, where N is any DNA nucleotide and is immediately 3′ of the gRNA recognition sequence of the non-complementary strand of the target DNA. As such, the PAM sequence of the complementary strand would be 5′-CCN-3′, where N is any DNA nucleotide and is immediately 5′ of the gRNA recognition sequence of the complementary strand of the target DNA.

A gRNA is an RNA molecule that binds to a Cas protein and targets the Cas protein to a specific location within a CIDEB genomic nucleic acid molecule. An exemplary gRNA is a gRNA effective to direct a Cas enzyme to bind to or cleave a CIDEB genomic nucleic acid molecule, wherein the gRNA comprises a DNA-targeting segment that hybridizes to a gRNA recognition sequence within the CIDEB genomic nucleic acid molecule that includes or is proximate to a position corresponding to positions: 14:24305635, 14:24305641, 14:24305650, 14:24305657, 14:24305662, 14:24305667, 14:24305671, 14:24305701, 14:24305709, 14:24305718, 14:24305721, 14:24305728, 14:24305743, 14:24305948, 14:24305966, 14:24305974, 14:24305980, 14:24305988, 14:24306014, 14:24306034, 14:24306041, 14:24306044, 14:24306047, 14:24306051, 14:24306064, 14:24306074, 14:24306077, 14:24306082, 14:24306083, 14:24306095, 14:24306122, 14:24306134, 14:24306373, 14:24306379, 14:24306382, 14:24306383, 14:24306426, 14:24306437, 14:24306439, 14:24306442, 14:24306444, 14:24306457, 14:24306463, 14:24306469, 14:24306480, 14:24306486, 14:24306504, 14:24306519, 14:24307382, 14:24307405, 14:24307417, 14:24307421, 14:24307441, 14:24307444, 14:24307444, 14:24307450, 14:24307461, 14:24307469, 14:24307474, 14:24307475, 14:24307833, 14:24307851, 14:24306426, 14:24307849, 14:24307448, 14:24305663, 14:24305686, 14:24307829, 14:24307818, 14:24307856, 14:24306423, 14:24306061, 14:24307390, 14:24306382, 14:24306373, 14:24305733, 14:24307858, 14:24306387, 14:24305637, 14:24306062, 14:24307853, 14:24307450, 14:24306052, 14:24305673, 14:24306043, 14:24307834, 14:24306417, 14:24307451, 14:24307436, 14:24305953, 14:24306489, 14:24307441, 14:24306375, 14:24305657, 14:24306427, 14:24306524, 14:24307516, 14:24307840, 14:24307501, 14:24305968, 14:24305986, 14:24307441, 14:24307459, 14:24306017, 14:24307424, 14:24306072, 14:24307423, 14:24307450, 14:24306420, 14:24307454, 14:24305653, 14:24307442, 14:24306002, 14:24306076, 14:24305664, 14:24305961, 14:24305706, 14:24305946, 14:24306455, 14:24307468, 14:24307825, 14:24306110, 14:24305710, 14:24307483, 14:24306459, 14:24305754, 14:24305650, 14:24305691, 14:24306508, 14:24306039, 14:24306139, 14:24306391, 14:24306373, 14:24307498, 14:24307415, 14:24306138, 14:24307453, 14:24305692, 14:24305683, 14:24307484, 14:24307385, 14:24306519, 14:24307839, 14:24305965, 14:24305988, 14:24306087, 14:24307439, 14:24307477, 14:24306436, 14:24306507, 14:24307397, 14:24307495, 14:24306034, 14:24306013, 14:24307381, 14:24306383, 14:24305638, 14:24307420, 14:24306020, 14:24306470, 14:24307435, 14:24306469, 14:24306451, 14:24306403, 14:24307515, 14:24307489, 14:24307414, 14:24306483, 14:24305755, 14:24305766, 14:24306064, 14:24307516, 14:24305766, 14:24306489, 14:24306097, 14:24305763, 14:24307447, 14:24307402, 14:24305972, 14:24306423, 14:24305974, 14:24307411, 14:24306121, 14:24307516, 14:24306424, 14:24306039, 14:24307853, 14:24306388, 14:24305990, 14:24307822, 14:24305640, 14:24307418, 14:24305758, 14:24306131, 14:24305953, 14:24305730, 14:24306418, 14:24306059, 14:24307842, 14:24307837, 14:24306095, 14:24306109, 14:24307822, 14:24306077, 14:24307824, 14:24306080, 14:24305649, 14:24306433, 14:24306420, 14:24305658, 14:24306472, 14:24307412, 14:24306062, 14:24306044, 14:24306047, 14:24306126, 14:24306449, 14:24307391, or 14:24307857 (according to GRCh38/hg38 human genome assembly coordinates). For example, a gRNA can be selected such that it hybridizes to a gRNA recognition sequence that is located from about 5, from about 10, from about 15, from about 20, from about 25, from about 30, from about 35, from about 40, from about 45, from about 50, from about 100, from about 200, from about 300, from about 400, from about 500, or from about 1,000 nucleotides of a position corresponding to: 14:24305635, 14:24305641, 14:24305650, 14:24305657, 14:24305662, 14:24305667, 14:24305671, 14:24305701, 14:24305709, 14:24305718, 14:24305721, 14:24305728, 14:24305743, 14:24305948, 14:24305966, 14:24305974, 14:24305980, 14:24305988, 14:24306014, 14:24306034, 14:24306041, 14:24306044, 14:24306047, 14:24306051, 14:24306064, 14:24306074, 14:24306077, 14:24306082, 14:24306083, 14:24306095, 14:24306122, 14:24306134, 14:24306373, 14:24306379, 14:24306382, 14:24306383, 14:24306426, 14:24306437, 14:24306439, 14:24306442, 14:24306444, 14:24306457, 14:24306463, 14:24306469, 14:24306480, 14:24306486, 14:24306504, 14:24306519, 14:24307382, 14:24307405, 14:24307417, 14:24307421, 14:24307441, 14:24307444, 14:24307444, 14:24307450, 14:24307461, 14:24307469, 14:24307474, 14:24307475, 14:24307833, 14:24307851, 14:24306426, 14:24307849, 14:24307448, 14:24305663, 14:24305686, 14:24307829, 14:24307818, 14:24307856, 14:24306423, 14:24306061, 14:24307390, 14:24306382, 14:24306373, 14:24305733, 14:24307858, 14:24306387, 14:24305637, 14:24306062, 14:24307853, 14:24307450, 14:24306052, 14:24305673, 14:24306043, 14:24307834, 14:24306417, 14:24307451, 14:24307436, 14:24305953, 14:24306489, 14:24307441, 14:24306375, 14:24305657, 14:24306427, 14:24306524, 14:24307516, 14:24307840, 14:24307501, 14:24305968, 14:24305986, 14:24307441, 14:24307459, 14:24306017, 14:24307424, 14:24306072, 14:24307423, 14:24307450, 14:24306420, 14:24307454, 14:24305653, 14:24307442, 14:24306002, 14:24306076, 14:24305664, 14:24305961, 14:24305706, 14:24305946, 14:24306455, 14:24307468, 14:24307825, 14:24306110, 14:24305710, 14:24307483, 14:24306459, 14:24305754, 14:24305650, 14:24305691, 14:24306508, 14:24306039, 14:24306139, 14:24306391, 14:24306373, 14:24307498, 14:24307415, 14:24306138, 14:24307453, 14:24305692, 14:24305683, 14:24307484, 14:24307385, 14:24306519, 14:24307839, 14:24305965, 14:24305988, 14:24306087, 14:24307439, 14:24307477, 14:24306436, 14:24306507, 14:24307397, 14:24307495, 14:24306034, 14:24306013, 14:24307381, 14:24306383, 14:24305638, 14:24307420, 14:24306020, 14:24306470, 14:24307435, 14:24306469, 14:24306451, 14:24306403, 14:24307515, 14:24307489, 14:24307414, 14:24306483, 14:24305755, 14:24305766, 14:24306064, 14:24307516, 14:24305766, 14:24306489, 14:24306097, 14:24305763, 14:24307447, 14:24307402, 14:24305972, 14:24306423, 14:24305974, 14:24307411, 14:24306121, 14:24307516, 14:24306424, 14:24306039, 14:24307853, 14:24306388, 14:24305990, 14:24307822, 14:24305640, 14:24307418, 14:24305758, 14:24306131, 14:24305953, 14:24305730, 14:24306418, 14:24306059, 14:24307842, 14:24307837, 14:24306095, 14:24306109, 14:24307822, 14:24306077, 14:24307824, 14:24306080, 14:24305649, 14:24306433, 14:24306420, 14:24305658, 14:24306472, 14:24307412, 14:24306062, 14:24306044, 14:24306047, 14:24306126, 14:24306449, 14:24307391, or 14:24307857 (according to GRCh38/hg38 human genome assembly coordinates). Other exemplary gRNAs comprise a DNA-targeting segment that hybridizes to a gRNA recognition sequence present within a CIDEB genomic nucleic acid molecule that includes or is proximate to the start codon or the stop codon. For example, a gRNA can be selected such that it hybridizes to a gRNA recognition sequence that is located from about 5, from about 10, from about 15, from about 20, from about 25, from about 30, from about 35, from about 40, from about 45, from about 50, from about 100, from about 200, from about 300, from about 400, from about 500, or from about 1,000 nucleotides of the start codon or located from about 5, from about 10, from about 15, from about 20, from about 25, from about 30, from about 35, from about 40, from about 45, from about 50, from about 100, from about 200, from about 300, from about 400, from about 500, or from about 1,000 nucleotides of the stop codon. Suitable gRNAs can comprise from about 17 to about 25 nucleotides, from about 17 to about 23 nucleotides, from about 18 to about 22 nucleotides, or from about 19 to about 21 nucleotides. In some embodiments, the gRNAs can comprise 20 nucleotides.

Examples of suitable gRNA recognition sequences located within the human CIDEB reference gene are set forth in Table 14 as SEQ ID NOs:25-37.

TABLE 14 Guide RNA Recognition Sequences Near CIDEB Variation(s) Strand gRNA Recognition Sequence SEQ ID NO: + AGCTGAGAGGTACTCCATGGTGG 25 + CAGAGCTGAGAGGTACTCCATGG 26 + GTCACCTGAGTAAGTCACTGGGG 27 + AGTCACCTGAGTAAGTCACTGGG 28 + CAGTCACCTGAGTAAGTCACTGG 29 + GCTTATATTAGATACTGACCTGG 30 − GTCAGTATCTAATATAAGCTCGG 31 − ATATAAGCTCGGAGTTTGGACGG 32 + CAGACACGGAAAGGTCGCTGGGG 33 + TTGTGATCACAGACACGGAAAGG 34 − TCCGTGTCTGTGATCACAAGCGG 35 − TCCGCTTGTGATCACAGACACGG 36 + AGCTGTCAGGCCTTTCCGGATGG 37

The Cas protein and the gRNA form a complex, and the Cas protein cleaves the target CIDEB genomic nucleic acid molecule. The Cas protein can cleave the nucleic acid molecule at a site within or outside of the nucleic acid sequence present in the target CIDEB, genomic nucleic acid molecule to which the DNA-targeting segment of a gRNA will bind. For example, formation of a CRISPR complex (comprising a gRNA hybridized to a gRNA recognition sequence and complexed with a Cas protein) can result in cleavage of one or both strands in or near (such as, for example, within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, or more base pairs from) the nucleic acid sequence present in the CIDEB genomic nucleic acid molecule to which a DNA-targeting segment of a gRNA will bind.

Such methods can result, for example, in a CIDEB genomic nucleic acid molecule in which a region of SEQ ID NO:1 is disrupted, the start codon is disrupted, the stop codon is disrupted, or the coding sequence is disrupted or deleted. Optionally, the cell can be further contacted with one or more additional gRNAs that hybridize to additional gRNA recognition sequences within the target genomic locus in the CIDEB genomic nucleic acid molecule. By contacting the cell with one or more additional gRNAs (such as, for example, a second gRNA that hybridizes to a second gRNA recognition sequence), cleavage by the Cas protein can create two or more double-strand breaks or two or more single-strand breaks.

In some embodiments, targeted genetic modifications of PNPLA3 genomic nucleic acid molecules can be generated by contacting a cell with a Cas protein and one or more gRNAs that hybridize to one or more gRNA recognition sequences within a target genomic locus in the PHPLA3 genomic nucleic acid molecule. For example, a gRNA recognition sequence can be located within a region of SEQ ID NO:43. For example, the gRNA recognition sequence can be located from about 1000, from about 500, from about 400, from about 300, from about 200, from about 100, from about 50, from about 45, from about 40, from about 35, from about 30, from about 25, from about 20, from about 15, from about 10, or from about 5 nucleotides of a position corresponding to position 5109 according to SEQ ID NO:43. Other exemplary gRNAs comprise a DNA-targeting segment that hybridizes to a gRNA recognition sequence present within a PNPLA3 genomic nucleic acid molecule that includes or is proximate to the start codon or the stop codon. For example, a gRNA can be selected such that it hybridizes to a gRNA recognition sequence that is located about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 100, about 200, about 300, about 400, about 500, or about 1,000 nucleotides from the start codon or located about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 100, about 200, about 300, about 400, about 500, or about 1,000 nucleotides from the stop codon. Suitable gRNAs can comprise from about 17 to about 25 nucleotides, from about 17 to about 23 nucleotides, from about 18 to about 22 nucleotides, or from about 19 to about 21 nucleotides. In some embodiments, the gRNAs comprise 20 nucleotides.

Examples of suitable gRNA recognition sequences located within the PNPLA3 reference gene are set forth in Table 15 as SEQ ID NOs:75-94.

TABLE 15 PNPLA3 Guide RNA Recognition Sequences Strand gRNA Recognition Sequence SEQ ID NO: + TCGGTCCAAAGACGAAGTCG 75 − CCTTCCGCACAAGATCTGAG 76 − TGTCGTACTCCCCATAGAAG 77 − ATGCATCCAAATATCCTCGA 78 − ACAACATGCGCGCGTCGCGG 79 − GGCATTTGCAGAGACCCTGT 80 + TTAAGCAAGTTCCTCCGACA 81 − GCGTCCCCAGACGCACCCAG 82 − CTCAGGATCCATCCCTTCTG 83 + TCTTACCAGAGTGTCTGATG 84 − AAGCTCTCGAGAGAAGGTAG 85 − GCAGAGGCGTAGACTGAGCT 86 + TAAAAGCGATATGTGGATGG 87 − CGAACAACATGCGCGCGTCG 88 + CTGGGAGAGATATGCCTTCG 89 + AGGTCCTCTCAGATCTTGTG 90 − CCAACTCACCTTGAGATCCG 91 − GGAGATGAGCTGGTGGACAT 92 + TCAGTCTACGCCTCTGCACA 93 − TCCAGGATGCTCTCATCCCA 94

The Cas protein and the gRNA form a complex, and the Cas protein cleaves the target PNPLA3 genomic nucleic acid molecule. The Cas protein can cleave the nucleic acid molecule at a site within or outside of the nucleic acid sequence present in the target PNPLA3, genomic nucleic acid molecule to which the DNA-targeting segment of a gRNA will bind. For example, formation of a CRISPR complex (comprising a gRNA hybridized to a gRNA recognition sequence and complexed with a Cas protein) can result in cleavage of one or both strands in or near (such as, for example, within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, or more base pairs from) the nucleic acid sequence present in the PNPLA3 genomic nucleic acid molecule to which a DNA-targeting segment of a gRNA will bind.

Such methods can result, for example, in a PNPLA3 genomic nucleic acid molecule in which a region of SEQ ID NO:43 is disrupted, the start codon is disrupted, the stop codon is disrupted, or the coding sequence is disrupted or deleted. Optionally, the cell can be further contacted with one or more additional gRNAs that hybridize to additional gRNA recognition sequences within the target genomic locus in the PNPLA3 genomic nucleic acid molecule. By contacting the cell with one or more additional gRNAs (such as, for example, a second gRNA that hybridizes to a second gRNA recognition sequence), cleavage by the Cas protein can create two or more double-strand breaks or two or more single-strand breaks.

In some embodiments, targeted genetic modifications of HSD17B13 genomic nucleic acid molecules can be generated by contacting a cell with a Cas protein and one or more gRNAs that hybridize to one or more gRNA recognition sequences within a target genomic locus in the PHPLA3 genomic nucleic acid molecule. For example, a gRNA recognition sequence can a DNA-targeting segment that hybridizes to a gRNA recognition sequence present within an HSD17B13 genomic nucleic acid molecule that includes or is proximate to the start codon or the stop codon. For example, a gRNA can be selected such that it hybridizes to a gRNA recognition sequence that is located about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 100, about 200, about 300, about 400, about 500, or about 1,000 nucleotides from the start codon or located about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 100, about 200, about 300, about 400, about 500, or about 1,000 nucleotides from the stop codon. Suitable gRNAs can comprise from about 17 to about 25 nucleotides, from about 17 to about 23 nucleotides, from about 18 to about 22 nucleotides, or from about 19 to about 21 nucleotides. In some embodiments, the gRNAs comprise 20 nucleotides.

Examples of suitable gRNA recognition sequences located within the HSD17B13 reference gene are set forth in Table 16 as SEQ ID NOs:95-114.

TABLE 16 HSD17613 Guide RNA Recognition Sequences Strand gRNA Recognition Sequence SEQ ID NO: − AGTGGGTGATGTAACAATCG 95 + TGAGGTAAGGAATCCCTTCG 96 + ACCTCTGTGAAAGCCAACAG 97 − TTCCTAATTACAGCGCGGTG 98 − ACATTTGAGGTCAACATCCT 99 + CACTCACCCAAAAATGTCCT 100 − CAATCGTGGTGAATAATGCT 101 + CTTCACCAACGACTCCAAGT 102 + ATACTTACCAATATGGGATG 103 − CGTCACTGCGCATGCGTATG 104 − AGCCGATCTTCTCAGCACCA 105 − ACAGAGCATATTGGTTCTGT 106 − GAGCTGGGCATGGAATAGGC 107 + CTGAAGCCACTGTGACGATG 108 − GCAGCTGAGTGCCGAAAACT 109 − AGCACTTCTTCCATCGATGA 110 − CTTCAGTGTGCGGCCACGAA 111 − AGAGGAGAAAATCTGTGGCT 112 − TCCTCAGAGGAGAAAATCTG 113 + GATGTTGACCTCAAATGTCT 114

The Cas protein and the gRNA form a complex, and the Cas protein cleaves the target HSD17B13 genomic nucleic acid molecule. The Cas protein can cleave the nucleic acid molecule at a site within or outside of the nucleic acid sequence present in the target HSD17B13, genomic nucleic acid molecule to which the DNA-targeting segment of a gRNA will bind. For example, formation of a CRISPR complex (comprising a gRNA hybridized to a gRNA recognition sequence and complexed with a Cas protein) can result in cleavage of one or both strands in or near (such as, for example, within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, or more base pairs from) the nucleic acid sequence present in the HSD17B13 genomic nucleic acid molecule to which a DNA-targeting segment of a gRNA will bind.

Such methods can also result, for example, in an HSD17B13 genomic nucleic acid molecule in which a region of SEQ ID NO:52 is disrupted, the start codon is disrupted, the stop codon is disrupted, or the coding sequence is disrupted or deleted. Optionally, the cell can be further contacted with one or more additional gRNAs that hybridize to additional gRNA recognition sequences within the target genomic locus in the HSD17B13 genomic nucleic acid molecule. By contacting the cell with one or more additional gRNAs (such as, for example, a second gRNA that hybridizes to a second gRNA recognition sequence), cleavage by the Cas protein can create two or more double-strand breaks or two or more single-strand breaks.

In some embodiments, the CIDEB inhibitor is a small molecule. In some embodiments, the CIDEB inhibitor is an antibody. In some embodiments, the CIDEB inhibitor comprises an inhibitory nucleic acid molecule, such as, for example an antisense nucleic acid molecule, an siRNA, or an shRNA.

In some embodiments, the PNPLA3 inhibitor is a small molecule. In some embodiments, the PNPLA3 inhibitor is an antibody. In some embodiments, the PNPLA3 inhibitor comprises an inhibitory nucleic acid molecule, such as, for example an antisense nucleic acid molecule, an siRNA, or an shRNA. An exemplary PNPLA3 inhibitor is AZD2693.

In some embodiments, the HSD17B13 inhibitor is a small molecule. Numerous HSD17B13 inhibitors are described in, for example, PCT Publications WO2019/183329, WO2019/183164, and WO2020/061177. In some embodiments, the HSD17B13 inhibitor is an antibody. In some embodiments, the HSD17B13 inhibitor comprises an inhibitory nucleic acid molecule, such as, for example an antisense nucleic acid molecule, an siRNA, or an shRNA. Additional examples of HSD17B13 inhibitors include, but are not limited to ARO-HSD or ALN-HSD.

In some embodiments, the dose of the CIDEB inhibitor can be reduced by about 10%, by about 20%, by about 30%, by about 40%, by about 50%, by about 60%, by about 70%, by about 80%, or by about 90% for subjects that are heterozygous for one or more CIDEB variant nucleic acid molecules compared to subjects that are CIDEB reference (who may receive a standard dosage amount). In some embodiments, the dose of the CIDEB inhibitor can be reduced by about 10%, by about 20%, by about 30%, by about 40%, or by about 50%. In addition, the dose of the CIDEB inhibitor in subjects that are heterozygous for one or more CIDEB variant nucleic acid molecules can be administered less frequently compared to subjects that are CIDEB reference. The dose can also be changed based on BMI, % liver fat, liver span, age, sex, etc.

In some embodiments, the dose of the PNPLA3 inhibitor can be increased by about 10%, by about 20%, by about 30%, by about 40%, by about 50%, by about 60%, by about 70%, by about 80%, or by about 90% for subjects that are heterozygous for one or more PNPLA3 variant nucleic acid molecules compared to subjects that are PNPLA3 reference (who may receive a standard dosage amount). In some embodiments, the dose of the PNPLA3 inhibitor can be increased by about 10%, by about 20%, by about 30%, by about 40%, or by about 50%. In addition, the dose of the PNPLA3 inhibitor in subjects that are heterozygous for one or more PNPLA3 variant nucleic acid molecules can be administered more frequently compared to subjects that are PNPLA3 reference.

In some embodiments, the dose of the HSD17B13 inhibitor can be reduced by about 10%, by about 20%, by about 30%, by about 40%, by about 50%, by about 60%, by about 70%, by about 80%, or by about 90% for subjects that are heterozygous for one or more HSD17B13 variant nucleic acid molecules compared to subjects that are HSD17B13 reference (who may receive a standard dosage amount). In some embodiments, the dose of the HSD17B13 inhibitor can be reduced by about 10%, by about 20%, by about 30%, by about 40%, or by about 50%. In addition, the dose of the HSD17B13 inhibitor in subjects that are heterozygous for one or more HSD17B13 variant nucleic acid molecules can be administered less frequently compared to subjects that are HSD17B13 reference.

In some embodiments, the methods further comprise detecting the presence or absence of a CIDEB variant nucleic acid molecule and/or a CIDEB predicted loss-of-function polypeptide in a biological sample from the subject. In some embodiments, the CIDEB variant nucleic acid molecule is a genomic nucleic acid molecule. In some embodiments, the CIDEB variant nucleic acid molecule is an mRNA molecule. In some embodiments, the CIDEB variant nucleic acid molecule is a cDNA molecule produced from an mRNA molecule. In some embodiments, the CIDEB variant nucleic acid molecule is a missense variant, a splice-site variant, a stop-gain variant, a start-loss variant, a stop-loss variant, a frameshift variant, or an in-frame indel variant, or a variant that encodes a truncated or mutated CIDEB polypeptide. In some embodiments, the CIDEB variant nucleic acid molecule comprises 14:24305635:A:AGTAG, 14:24305641:A:C, 14:24305650:G:A, 14:24305657:C:A, 14:24305662:G:T, 14:24305667:T:C, 14:24305671:C:A, 14:24305671:C:G, 14:24305701:A:T, 14:24305709:C:T, 14:24305718:A:G, 14:24305721:T:C, 14:24305728:G:GGCCTT, 14:24305743:T:C, 14:24305948:T:C, 14:24305966:C:T, 14:24305974:T:C, 14:24305980:TCA:T, 14:24305988:C:T, 14:24306014:C:T, 14:24306034:A:C, 14:24306041:C:G, 14:24306044:G:A, 14:24306047:G:A, 14:24306051:T:G, 14:24306064:T:C, 14:24306074:A:G, 14:24306077:G:C, 14:24306082:A:G, 14:24306083:T:A, 14:24306095:G:A, 14:24306122:A:G, 14:24306134:C:G, 14:24306373:C:G, 14:24306379:T:C, 14:24306382:G:A, 14:24306383:G:T, 14:24306426:T:G, 14:24306437:C:G, 14:24306439:G:C, 14:24306442:A:G, 14:24306444:A:G, 14:24306457:C:T, 14:24306463:C:T, 14:24306469:C:T, 14:24306480:A:G, 14:24306486:A:C, 14:24306504:A:G, 14:24306519:A:G, 14:24307382:G:C, 14:24307405:A:G, 14:24307417:A:T, 14:24307421:T:A, 14:24307441:C:A, 14:24307444:A:C, 14:24307444:A:G, 14:24307450:C:CGCTG, 14:24307461:TG:T, 14:24307469:AG:A, 14:24307474:C:T, 14:24307475:A:G, 14:24307833:G:C, 14:24307851:T:TAC, 14:24306426:T:C, 14:24307849:G:C, 14:24307448:G:T, 14:24305671:C:T, 14:24305663:C:T, 14:24305686:C:G, 14:24307829:A:C, 14:24307818:CTGAG:C, 14:24307856:C:T, 14:24306423:T:C, 14:24306061:AC:A, 14:24307390:C:T, 14:24306382:G:T, 14:24306373:C:T, 14:24305733:T:C, 14:24307858:T:C, 14:24306387:C:T, 14:24305637:T:C, 14:24306062:C:T, 14:24307853:C:G, 14:24307450:C:G, 14:24306052:TG:T, 14:24305673:G:A, 14:24306043:C:T, 14:24307834:G:A, 14:24306417:C:T, 14:24307451:G:A, 14:24307436:A:C, 14:24305953:ACTTT:A, 14:24306489:G:T, 14:24307441:C:T, 14:24306375:C:T, 14:24305657:C:G, 14:24306427:C:T, 14:24306524:C:T, 14:24307516:C:A, 14:24307840:G:C, 14:24307501:A:G, 14:24305968:A:C, 14:24305986:C:T, 14:24307441:C:G, 14:24307459:G:T, 14:24306017:T:A, 14:24307424:G:A, 14:24306072:G:T, 14:24307423:C:T, 14:24307450:C:T, 14:24306420:G:A, 14:24307454:G:A, 14:24305653:C:T, 14:24307442:G:A, 14:24306002:C:T, 14:24306076:C:T, 14:24305664:C:T, 14:24305961:TG:T, 14:24305706:A:G, 14:24305946:C:T, 14:24306455:G:C, 14:24307468:G:A, 14:24307825:A:C, 14:24306110:G:A, 14:24305710:C:T, 14:24307483:C:T, 14:24306459:A:G, 14:24305754:C:T, 14:24305650:G:C, 14:24305691:C:T, 14:24306508:G:C, 14:24306039:G:T, 14:24306139:T:C, 14:24306391:T:C, 14:24306373:C:A, 14:24307498:C:T, 14:24307415:G:A, 14:24306138:CTG:C, 14:24307453:T:C, 14:24305692:G:A, 14:24305683:C:G, 14:24307484:G:A, 14:24307385:C:T, 14:24306519:A:T, 14:24307839:A:C, 14:24305965:C:T, 14:24305988:CAT:C, 14:24306087:C:G, 14:24307439:C:T, 14:24307477:A:C, 14:24306436:G:T, 14:24306507:A:G, 14:24307397:C:T, 14:24307495:G:A, 14:24306034:A:T, 14:24306013:G:A, 14:24307381:A:G, 14:24306383:G:C, 14:24305638:A:G, 14:24307420:G:A, 14:24306020:C:T, 14:24306470:A:C, 14:24307435:C:T, 14:24306469:C:G, 14:24306451:C:T, 14:24306403:G:A, 14:24307515:C:G, 14:24307489:A:G, 14:24307414:C:T, 14:24306483:A:G, 14:24305755:G:A, 14:24305766:C:T, 14:24306064:T:G, 14:24307516:C:G, 14:24305766:C:G, 14:24306489:G:A, 14:24306097:T:C, 14:24305763:T:G, 14:24307447:G:A, 14:24307402:G:A, 14:24305972:C:G, 14:24306423:T:G, 14:24305974:T:TG, 14:24307411:T:C, 14:24306121:T:C, 14:24307516:C:T, 14:24306424:C:T, 14:24306039:G:C, 14:24307853:C:A, 14:24306388:A:G, 14:24305990:T:C, 14:24307822:G:GT, 14:24305640:G:A, 14:24307418:T:C, 14:24305758:G:C, 14:24306131:C:T, 14:24305953:A:G, 14:24305730:C:A, 14:24306418:A:G, 14:24306059:AC:A, 14:24307842:G:A, 14:24307837:T:G, 14:24306095:G:T, 14:24306109:C:T, 14:24307822:G:A, 14:24306077:G:A, 14:24307824:A:T, 14:24306080:C:T, 14:24305649:C:T, 14:24306433:G:GA, 14:24306420:G:C, 14:24305658:T:G, 14:24306472:C:T, 14:24307412:TC:T, 14:24306062:C:A, 14:24306044:G:C, 14:24306047:G:T, 14:24306126:CAG:C, 14:24306449:C:G, 14:24307391:G:A, or 14:24307857:A:C (according to GRCh38/hg38 human genome assembly coordinates).

Detecting the presence or absence of a CIDEB variant nucleic acid molecule in a biological sample from a subject and/or determining whether a subject has a CIDEB variant nucleic acid molecule can be carried out by any of the methods described herein. In some embodiments, these methods can be carried out in vitro. In some embodiments, these methods can be carried out in situ. In some embodiments, these methods can be carried out in vivo. In any of these embodiments, the nucleic acid molecule can be present within a cell obtained from the subject.

In some embodiments, the detecting step comprises obtaining or having obtained a biological sample from the subject, and performing or having performed an assay on the biological sample to determine whether the subject has the CIDEB variant nucleic acid molecule, and/or a CIDEB predicted loss-of-function polypeptide. In some embodiments, the assay is a sequence analysis that comprises sequencing at least a portion of the nucleotide sequence of the CIDEB genomic nucleic acid molecule in the biological sample. In some embodiments, the assay is a sequence analysis that comprises sequencing at least a portion of the nucleotide sequence of the CIDEB mRNA molecule in the biological sample. In some embodiments, the assay is a sequence analysis that comprises sequencing at least a portion of the nucleotide sequence of the CIDEB cDNA molecule produced from an mRNA molecule in the biological sample.

In some embodiments, the sequence analysis comprises: a) contacting the biological sample with a primer hybridizing to a portion of the nucleotide sequence of the CIDEB nucleic acid molecule that is proximate to a CIDEB variant nucleic acid molecule position; b) extending the primer at least through the CIDEB variant nucleic acid molecule position; and c) determining whether the extension product of the primer comprises a variant nucleotide at the CIDEB variant nucleic acid molecule position. In some embodiments, the sequence analysis comprises sequencing the entire nucleic acid molecule in the biological sample.

In some embodiments, the assay is a sequence analysis that comprises: a) amplifying at least a portion of the CIDEB nucleic acid molecule in the biological sample, wherein the portion comprises a CIDEB variant nucleic acid molecule position; b) labeling the amplified nucleic acid molecule with a detectable label; c) contacting the labeled nucleic acid molecule with a support comprising an alteration-specific probe, wherein the alteration-specific probe comprises a nucleotide sequence which hybridizes under stringent conditions to the CIDEB variant nucleic acid molecule position; and d) detecting the detectable label. In some embodiments, the CIDEB nucleic acid molecule in the biological sample is mRNA and the mRNA is reverse-transcribed into cDNA prior to the amplifying step.

In some embodiments, the assay is a sequence analysis that comprises contacting the CIDEB nucleic acid molecule in the biological sample with an alteration-specific probe comprising a detectable label, wherein the alteration-specific probe comprises a nucleotide sequence which hybridizes under stringent conditions to a CIDEB variant nucleic acid molecule position, and detecting the detectable label.

In some embodiments, the assay is an immunoassay for detecting the presence of a CIDEB predicted loss-of-function polypeptide. In some embodiments, mass spectrometry is used for detecting the presence of a CIDEB predicted loss-of-function polypeptide.

In some embodiments, the methods further comprise determining the subject's gene burden of having a CIDEB variant nucleic acid molecule and/or a CIDEB predicted loss-of-function polypeptide. When the subject has a lower gene burden, the subject is administered or continued to be administered the CIDEB inhibitor in a standard dosage amount. When the subject has a greater gene burden, the subject is administered or continued to be administered the CIDEB inhibitor in an amount that is the same as or less than the standard dosage amount. In some embodiments, the subject's gene burden represents a weighted sum of a plurality of genetic variants associated with protection against developing a liver disease. In some embodiments, the gene burden is calculated using at least about 2, at least about 3, at least about 4, at least about 5, at least about 10, at least about 20, at least about 30, at least about 40, at least about 50, at least about 60, at least about 70, at least about 80, at least about 100, at least about 120, at least about 150, at least about 200, at least about 250, at least about 300, at least about 400, at least about 500, or at least about 1,000 genetic variants associated with liver disease. In some embodiments, the gene burden may be divided into quintiles, e.g., top quintile, intermediate quintile, and bottom quintile, wherein the top quintile of gene burden corresponds to the lowest risk group and the bottom quintile of gene burden corresponds to the highest risk group.

The sequence analysis to determine whether a subject has a CIDEB variant nucleic acid molecule can be carried out by any of the methods described herein. In some embodiments, these methods can be carried out in vitro. In some embodiments, these methods can be carried out in situ. In some embodiments, these methods can be carried out in vivo. In any of these embodiments, the nucleic acid molecule can be present within a cell obtained from the subject.

In some embodiments, the methods further comprise detecting the presence or absence of a PNPLA3 variant nucleic acid molecule encoding PNPLA3 Ile148Met or PNPLA3 Ile144Met polypeptide and/or a PNPLA3 Ile148Met or a PNPLA3 Ile144Met polypeptide in a biological sample from the subject. In some embodiments, the PNPLA3 variant nucleic acid molecule is a genomic DNA molecule comprising a guanine at a position corresponding to position 5109 according to SEQ ID NO:43; an mRNA molecule comprising a guanine at a position corresponding to position 444 according to SEQ ID NO:46, or a guanine at a position corresponding to position 432 according to SEQ ID NO:47; a cDNA molecule produced from an mRNA molecule, wherein the cDNA molecule has a nucleotide sequence comprising: a guanine at a position corresponding to position 444 according to SEQ ID NO: 50, or a guanine at a position corresponding to position 432 according to SEQ ID NO:51.

Detecting the presence or absence of a PNPLA3 variant nucleic acid molecule encoding PNPLA3 Ile148Met or PNPLA3 Ile144Met polypeptide in a biological sample from a subject and/or determining whether a subject has a PNPLA3 variant nucleic acid molecule encoding PNPLA3 Ile148Met or PNPLA3 Ile144Met polypeptide can be carried out by any of the methods described herein. In some embodiments, these methods can be carried out in vitro. In some embodiments, these methods can be carried out in situ. In some embodiments, these methods can be carried out in vivo. In any of these embodiments, the nucleic acid molecule can be present within a cell obtained from the subject.

In some embodiments, the detecting step comprises obtaining or having obtained a biological sample from the subject, and performing or having performed an assay on the biological sample to determine whether the subject has: i) a PNPLA3 genomic nucleic acid molecule comprising a guanine at a position corresponding to position 5109 according to SEQ ID NO:43, or a complement thereof; ii) a PNPLA3 mRNA molecule comprising: a guanine at a position corresponding to position 444 according to SEQ ID NO:46, or a guanine at a position corresponding to position 432 according to SEQ ID NO:47, or a complement thereof; or iii) a PNPLA3 cDNA molecule comprising: a guanine at a position corresponding to position 444 according to SEQ ID NO: 50, or a guanine at a position corresponding to position 432 according to SEQ ID NO:51, or a complement thereof.

In some embodiments, the sequence analysis comprises: a) contacting the biological sample with a primer hybridizing to: i) a portion of the nucleotide sequence of the PNPLA3 genomic nucleic acid molecule, or a complement thereof, that is proximate to a position corresponding to position 5109 according to SEQ ID NO:43; ii) a portion of the nucleotide sequence of the PNPLA3 mRNA molecule, or the complement thereof, that is proximate to a position corresponding to position 444 according to SEQ ID NO:46, or position 432 according to SEQ ID NO:47; or iii) a portion of the nucleotide sequence of the PNPLA3 cDNA molecule, or the complement thereof, that is proximate to a position corresponding to position 444 according to SEQ ID NO:50, or position 432 according to SEQ ID NO:51; b) extending the primer at least through: i) position of the nucleotide sequence of PNPLA3 genomic nucleic acid molecule, or a complement thereof corresponding to position corresponding to position 5109 according to SEQ ID NO:43; ii) position of the nucleotide sequence of PNPLA3 mRNA molecule, or a complement thereof corresponding to a position corresponding to position 444 according to SEQ ID NO:46, or position 432 according to SEQ ID NO:47; or iii) position of the nucleotide sequence of PNPLA3 cDNA molecule, or a complement thereof corresponding to a position corresponding to position 444 according to SEQ ID NO:50, or position 432 according to SEQ ID NO:51; and c) determining whether the extension product of the primer comprises: a guanine at a position corresponding to position 5109 according to SEQ ID NO:43, or a complement thereof; a guanine at a position corresponding to position 444 according to SEQ ID NO:46, or a guanine at a position corresponding to position 432 according to SEQ ID NO:47, or a complement thereof; or a guanine at a position corresponding to position 444 according to SEQ ID NO:50, or a guanine at a position corresponding to position 432 according to SEQ ID NO:51, or a complement thereof.

In some embodiments, the assay is a sequence analysis that comprises a) amplifying at least a portion of: i) a PNPLA3 genomic nucleic acid molecule comprising a guanine at a position corresponding to position 5109 according to SEQ ID NO:43, or a complement thereof; ii) a PNPLA3 mRNA molecule comprising: a guanine at a position corresponding to position 444 according to SEQ ID NO:46, or a guanine at a position corresponding to position 432 according to SEQ ID NO:47, or a complement thereof; or iii) a PNPLA3 cDNA molecule comprising: a guanine at a position corresponding to position 444 according to SEQ ID NO: 50, or a guanine at a position corresponding to position 432 according to SEQ ID NO:51; b) labeling the amplified nucleic acid molecule with a detectable label; c) contacting the labeled nucleic acid molecule with a support comprising an alteration-specific probe, wherein the alteration-specific probe comprises a nucleotide sequence which hybridizes under stringent conditions to the nucleotide sequence of the amplified nucleic acid molecule comprising: i) a guanine at a position corresponding to position 5109 according to SEQ ID NO:43, or a complement thereof; ii) a guanine at a position corresponding to position 444 according to SEQ ID NO:46, or a guanine at a position corresponding to position 432 according to SEQ ID NO:47, or a complement thereof; or iii) a guanine at a position corresponding to position 444 according to SEQ ID NO:50, or a guanine at a position corresponding to position 432 according to SEQ ID NO:51, or a complement thereof; and d) detecting the detectable label.

In some embodiments, the assay is a sequence analysis that comprises contacting the PNPLA3 nucleic acid molecule in the biological sample with an alteration-specific probe comprising a detectable label, wherein the alteration-specific probe comprises a nucleotide sequence which hybridizes under stringent conditions to: i) a PNPLA3 genomic nucleic acid molecule comprising a guanine at a position corresponding to position 5109 according to SEQ ID NO:43, or a complement thereof; ii) a PNPLA3 mRNA molecule comprising: a guanine at a position corresponding to position 444 according to SEQ ID NO:46, or a guanine at a position corresponding to position 432 according to SEQ ID NO:47, or a complement thereof; or iii) a PNPLA3 cDNA molecule comprising: a guanine at a position corresponding to position 444 according to SEQ ID NO: 50, or a guanine at a position corresponding to position 432 according to SEQ ID NO:51; and detecting the detectable label.

The sequence analysis to determine whether a subject has a PNPLA3 variant nucleic acid molecule encoding a PNPLA3 predicted loss-of-function polypeptide can be carried out by any of the methods described herein. In some embodiments, these methods can be carried out in vitro. In some embodiments, these methods can be carried out in situ. In some embodiments, these methods can be carried out in vivo. In any of these embodiments, the nucleic acid molecule can be present within a cell obtained from the subject.

In some embodiments, the assay is an immunoassay for detecting the presence of a PNPLA3 Ile148Met or Ile144Met variant polypeptide. In some embodiments, mass spectrometry is used for detecting the presence of a PNPLA3 Ile148Met or Ile144Met variant polypeptide.

In some embodiments, the methods further comprise detecting the presence or absence of a nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide and/or a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide in a biological sample from the subject. In some embodiments, the nucleic acid molecule encoding the reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide comprises: a genomic nucleic acid molecule comprising the nucleotide sequence according to SEQ ID NO:52, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:52 and encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide; an mRNA molecule comprising the nucleotide sequence according to any one of SEQ ID NOs:53-62 or a nucleotide sequence having at least 90% sequence identity to SEQ ID NOs:53-62 and encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide; or a cDNA molecule comprising the nucleotide sequence according to any one of SEQ ID NOs:63-72 or a nucleotide sequence having at least 90% sequence identity to SEQ ID NOs:63-72 and encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide.

Detecting the presence or absence of a nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide and/or determining whether a subject has a nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide can be carried out by any of the methods described herein. In some embodiments, these methods can be carried out in vitro. In some embodiments, these methods can be carried out in situ. In some embodiments, these methods can be carried out in vivo. In any of these embodiments, the nucleic acid molecule can be present within a cell obtained from the subject.

In some embodiments, the detecting step comprises obtaining or having obtained a biological sample from the subject; and performing or having performed an assay on the biological sample to determine whether the subject has: i) an HSD17B13 genomic nucleic acid molecule comprising SEQ ID NO:52, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:52 and encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide; ii) an HSD17B13 mRNA molecule comprising any one of SEQ ID NOs:53-62, or a nucleotide sequence having at least 90% sequence identity to any one of SEQ ID NOs:53-62 and encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide; or iii) an HSD17B13 cDNA molecule comprising any one of SEQ ID NOs:63-72, or a nucleotide sequence having at least 90% sequence identity to any one of SEQ ID NOs:63-72 and encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide.

In some embodiments, the sequence analysis comprises sequencing at least a portion of the nucleotide sequence of the HSD17B13 genomic nucleic acid molecule, mRNA molecule, or cDNA molecule produced from mRNA molecule in the biological sample.

In some embodiments, the assay is an immunoassay for detecting the presence of an HSD17B13 wild type or reference polypeptide. In some embodiments, mass spectrometry is used for detecting the presence of an HSD17B13 wild type or reference polypeptide.

In any of the embodiments described herein, when the subject is CIDEB reference, the subject can be administered the CIDEB inhibitor in a standard dosage amount. When the subject is heterozygous for a CIDEB variant nucleic acid molecule encoding a CIDEB predicted loss-of-function polypeptide, the subject can be administered the CIDEB inhibitor in a dosage amount that is the same as or less than a standard dosage amount. The CIDEB inhibitor can also be administered in combination with one or more PNPLA3 inhibitors and/or one or more HSD17B13 inhibitors.

In any of the embodiments described herein, when the subject is CIDEB reference or is heterozygous for a CIDEB variant nucleic acid molecule and is also a carrier for a nucleic acid molecule encoding a PNPLA3 Ile148Met or an Ile144Met polypeptide, such a subject can be treated with a combination of one or more CIDEB inhibitors, one or more PNPLA3 inhibitors and/or one or more HSD17B13 inhibitors.

In any of the embodiments described herein, when the subject is homozygous for a nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide, the subject is administered a CIDEB inhibitor in an amount that is the same as or greater than a standard dosage amount, or is administered a combination of a CIDEB inhibitor in an amount that is the same as or greater than a standard dosage amount, an HSD17B13 inhibitor, and/or a PNPLA3 inhibitor. When the subject is not homozygous for a nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide (i.e., is a carrier for a loss-of-function HSD17B13), the subject is administered a CIDEB inhibitor in an amount that is less than a standard dosage amount, or is administered a combination of a CIDEB inhibitor in an amount that is less than a standard dosage amount, an HSD17B13 inhibitor, and/or a PNPLA3 inhibitor.

In some embodiments, when the subject is CIDEB reference, the subject is also administered a therapeutic agent that treats or inhibits liver disease in a standard dosage amount. In some embodiments, when the subject is heterozygous for a CIDEB variant nucleic acid molecule, the subject is also administered a therapeutic agent that treats or inhibits liver disease in a dosage amount that is the same as or less than a standard dosage amount.

In some embodiments, the treatment methods further comprise detecting the presence or absence of a CIDEB predicted loss-of-function polypeptide in a biological sample from the subject. In some embodiments, when the subject does not have a CIDEB predicted loss-of-function or polypeptide, the subject is also administered a therapeutic agent that treats or inhibits liver disease in a standard dosage amount. In some embodiments, when the subject has a CIDEB predicted loss-of-function polypeptide, the subject is also administered a therapeutic agent that treats or inhibits liver disease in a dosage amount that is the same as or less than a standard dosage amount.

In some embodiments, the treatment methods further comprise detecting the presence or absence of a PNPLA3 Ile148Met or an Ile144Met polypeptide in a biological sample from the subject. In some embodiments, when the subject has a CIDEB predicted loss-of-function polypeptide and a PNPLA3 Ile148Met or an Ile144Met polypeptide, the subject is also administered a therapeutic agent that treats or inhibits liver disease in a dosage amount that is the same as or greater than a standard dosage amount.

In some embodiments, the treatment methods further comprise detecting the presence or absence of a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide in a biological sample from the subject. In some embodiments, when the subject is homozygous for a nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide, the subject is administered a CIDEB inhibitor in an amount that is the same as or greater than a standard dosage amount, or is administered a combination of a CIDEB inhibitor in an amount that is the same as or greater than a standard dosage amount, an HSD17B13 inhibitor, and/or a PNPLA3 inhibitor. When the subject is not homozygous for a nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide (i.e., is a carrier for a loss-of-function HSD17B13), the subject is administered a CIDEB inhibitor in an amount that is less than a standard dosage amount, or is administered a combination of a CIDEB inhibitor in an amount that is less than a standard dosage amount, an HSD17B13 inhibitor, and/or a PNPLA3 inhibitor.

The present disclosure also provides methods of treating a subject with a CIDEB inhibitor, wherein the subject has a liver disease or is at risk of developing a liver disease. The methods comprise determining whether the subject has a CIDEB variant nucleic acid molecule by obtaining or having obtained a biological sample from the subject, and performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising the CIDEB variant nucleic acid molecule. When the subject is CIDEB reference, the method further comprises administering or continuing to administer to the subject the CIDEB inhibitor in a standard dosage amount. When the subject is heterozygous for the CIDEB variant nucleic acid molecule, the method further comprises administering or continuing to administer to the subject the CIDEB inhibitor in a dosage amount that is the same as or less than a standard dosage amount. The presence of a genotype having the CIDEB variant nucleic acid molecule indicates the subject has a decreased risk of developing the liver disease or has a decreased risk of developing a more severe form of the liver disease. Determining whether the subject has a genotype comprising the CIDEB variant nucleic acid molecule can be carried out as described herein.

In some embodiments, the subject is CIDEB reference, and the subject is administered or continued to be administered the CIDEB inhibitor in a standard dosage amount. In some embodiments, the subject is heterozygous for the CIDEB variant nucleic acid molecule, and the subject is administered or continued to be administered the CIDEB inhibitor in a dosage amount that is the same as or less than a standard dosage amount.

In some embodiments, the subject is CIDEB reference or is heterozygous for the CIDEB variant nucleic acid molecule and the subject is a carrier of a nucleic acid molecule encoding a PNPLA3 Ile148Met or an Ile144Met polypeptide, the subject is administered or continued to be administered the CIDEB inhibitor and is also administered a PNPLA3 inhibitor and/or an HSD17B13 inhibitor.

In some embodiments, the subject is CIDEB reference or heterozygous for the CIDEB variant nucleic acid molecule and the subject is a carrier of a nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide, the subject is administered or continued to be administered the CIDEB inhibitor and is also administered an HSD17B13 inhibitor and/or a PNPLA3 inhibitor.

In any of the embodiments described herein, the method can further comprise administering a therapeutic agent for treating a liver disease to the subject.

In some embodiments, the subject being treated with the CIDEB inhibitor, the PNPLA3 inhibitor, or the HSD17B13 inhibitor, or any combination thereof, has excessive weight, has elevated BMI, is obese, has elevated body fat mass, has elevated percentage of liver fat, has elevated body fat percentage, has elevated body fat volume, and/or has excessive food intake. In some embodiments, the subject is obese. In some embodiments, the subject has excessive weight. In some embodiments, the subject has elevated BMI. In some embodiments, the subject has elevated body fat mass. In some embodiments, the subject has elevated body fat percentage. In some embodiments, the subject has elevated percentage of liver fat. In some embodiments, the subject has elevated body fat volume. In some embodiments, the subject has excessive food intake. In such subjects, the CIDEB inhibitor, the PNPLA3 inhibitor, or the HSD17B13 inhibitor, or any combination thereof, is administered to treat or prevent the complications of liver injury, liver fat accumulation, liver inflammation, fibrosis, liver cirrhosis or its comorbidities. In some embodiments, the CIDEB inhibitor, the PNPLA3 inhibitor, or the HSD17B13 inhibitor, or any combination thereof, is administered to treat or prevent the complications of liver injury, liver fat accumulation, liver inflammation, fibrosis, liver cirrhosis, or its comorbidities. In some embodiments, the CIDEB inhibitor, the PNPLA3 inhibitor, the HSD17B13 inhibitor, or any combination thereof, is administered to treat or prevent the complications of liver injury. In some embodiments, the CIDEB inhibitor, the PNPLA3 inhibitor, or the HSD17B13 inhibitor, or any combination thereof, is administered to treat or prevent the complications of liver fat accumulation. In some embodiments, the CIDEB inhibitor, the PNPLA3 inhibitor, or the HSD17B13 inhibitor, or any combination thereof, is administered to treat or prevent the complications of liver inflammation. In some embodiments, the CIDEB inhibitor, the PNPLA3 inhibitor, or the HSD17B13 inhibitor, or any combination thereof, is administered to treat or prevent the complications of fibrosis. In some embodiments, the CIDEB inhibitor, the PNPLA3 inhibitor, or the HSD17B13 inhibitor, or any combination thereof, is administered to treat or prevent the complications of liver cirrhosis or its comorbidities. In some embodiments, BMI is measured, body fat is determined, or fat distribution is determined to determine if the CIDEB inhibitor, the PNPLA3 inhibitor, or the HSD17B13 inhibitor, or any combination thereof, has to be used or used in different doses or patterns of administration. In some embodiments, BMI is measured. In some embodiments, body fat is determined. In some embodiments, fat distribution is determined. In some embodiments, the dosage of the CIDEB inhibitor, the PNPLA3 inhibitor, or the HSD17B13 inhibitor, or any combination thereof, can be increased upon an increase in any one or more of weight, BMI, obesity, body fat mass, liver fat percentage, body fat percentage, body fat volume, and/or food intake.

In some embodiments, the subject being treated with a CIDEB inhibitor, HSD17B13 inhibitor, and/or a PNPLA3 inhibitor is heterozygous or homozygous for a nucleic acid molecule encoding a PNPLA3 Ile148Met or Ile144Met polypeptide. In some embodiments, the subject being treated and having the PNPLA3 Ile148Met or Ile144Met polypeptide is administered the CIDEB inhibitor, the HSD17B13 inhibitor, and/or the PNPLA3 inhibitor to treat or prevent the complications of liver injury, liver fat accumulation, liver inflammation, fibrosis, liver cirrhosis or its comorbidities. In some embodiments, the CIDEB inhibitor, the HSD17B13 inhibitor, and/or the PNPLA3 inhibitor is administered to treat or prevent the complications of liver injury, liver fat accumulation, liver inflammation, fibrosis, liver cirrhosis or its comorbidities. In some embodiments, the CIDEB inhibitor, the HSD17B13 inhibitor, and/or the PNPLA3 inhibitor is administered to treat or prevent the complications of liver injury. In some embodiments, the CIDEB inhibitor, the HSD17B13 inhibitor, and/or the PNPLA3 inhibitor is administered to treat or prevent the complications of liver fat accumulation. In some embodiments, the CIDEB inhibitor, the HSD17B13 inhibitor, and/or the PNPLA3 inhibitor is administered to treat or prevent the complications of liver inflammation. In some embodiments, the CIDEB inhibitor, the HSD17B13 inhibitor, and/or the PNPLA3 inhibitor is administered to treat or prevent the complications of fibrosis. In some embodiments, the CIDEB inhibitor, the HSD17B13 inhibitor, and/or the PNPLA3 inhibitor is administered to treat or prevent the complications of liver cirrhosis or its comorbidities. In some embodiments, the methods further comprise genetic testing for the PNPLA3 Ile148Met or Ile144Met polypeptide to determine if the PNPLA3 inhibitor has to be used or used in a different dose or pattern of administration.

The present disclosure also provides methods of treating a subject having a liver disease or is at risk of developing a liver disease and who is heterozygous or homozygous for a nucleic acid molecule encoding a PNPLA3 Ile148Met or Ile144Met polypeptide, the methods comprising administering a CIDEB inhibitor, an HSD17B13 inhibitor, and/or a PNPLA3 inhibitor to the subject.

The amino acid sequences for two reference PNPLA3 polypeptides are set forth in SEQ ID NO:38 and SEQ ID NO:39. The reference PNPLA3 polypeptide having SEQ ID NO:38 is 481 amino acids in length, whereas the reference PNPLA3 polypeptide having SEQ ID NO:39 is 477 amino acids in length. The reference PNPLA3 polypeptide having SEQ ID NO:38 has an isoleucine at position 148. The reference PNPLA3 polypeptide having SEQ ID NO:39 has an isoleucine at position 144.

The PNPLA3 Ile148Met polypeptide comprises an amino acid sequence set forth in SEQ ID NO:40, where the isoleucine at position 148 is replaced with a methionine. The PNPLA3 Ile144Met polypeptide comprises an amino acid sequence set forth in SEQ ID NO:41, where the isoleucine at position 144 is replaced with a methionine.

The nucleotide sequence of a PNPLA3 genomic nucleic acid molecule encoding a reference PNPLA3 polypeptide is set forth in SEQ ID NO:42. The reference PNPLA3 genomic nucleic acid molecule having SEQ ID NO:42 comprises a cytosine at position 5109. The reference PNPLA3 genomic nucleic acid molecule having SEQ ID NO:42 comprises an ATC codon at positions 5107 to 5109.

The nucleotide sequence of a PNPLA3 variant genomic nucleic acid molecule encoding the PNPLA3 Ile148Met and Ile144Met polypeptide is set forth in SEQ ID NO:43, wherein the cytosine at the position corresponding to position 5109 of the reference PNPLA3 genomic nucleic acid molecule (according to SEQ ID NO:42) is replaced with a guanine, and the ATC codon at the positions corresponding to positions 5107 to 5109 of the reference PNPLA3 genomic DNA molecule (according to SEQ ID NO:42) is replaced by an ATG codon.

The nucleotide sequence of a PNPLA3 mRNA molecule encoding a PNPLA3 reference polypeptide having SEQ ID NO:38 is set forth in SEQ ID NO:44. The mRNA molecule encoding the PNPLA3 reference polypeptide having SEQ ID NO:38 comprises a cytosine at position 444. The mRNA molecule encoding the PNPLA3 reference polypeptide having SEQ ID NO:38 comprises an AUC codon at the positions 442 to 444. The nucleotide sequence of a PNPLA3 mRNA molecule encoding a PNPLA3 reference polypeptide having SEQ ID NO:39 is set forth in SEQ ID NO:45. The mRNA molecule encoding the PNPLA3 reference polypeptide having SEQ ID NO:39 comprises a cytosine at position 432. The mRNA molecule encoding the PNPLA3 reference polypeptide having SEQ ID NO:39 comprises an AUC codon at positions 430 to 432.

The nucleotide sequence of a PNPLA3 mRNA molecule encoding a PNPLA3 Ile148Met polypeptide is set forth in SEQ ID NO:46, wherein the cytosine at the position corresponding to position 444 of the PNPLA3 reference mRNA molecule (according to SEQ ID NO:44) is replaced with a guanine, and the AUC codon at positions corresponding to positions 442 to 444 of the PNPLA3 reference mRNA molecule (according to SEQ ID NO:44) is replaced by an AUG codon. The nucleotide sequence of a PNPLA3 mRNA molecule encoding a PNPLA3 Ile144Met polypeptide is set forth in SEQ ID NO:47, wherein the cytosine at the position corresponding to position 432 of the PNPLA3 reference mRNA molecule (according to SEQ ID NO:45) is replaced with a guanine, and the AUC codon at the positions corresponding to positions 430 to 432 of the PNPLA3 reference mRNA molecule (according to SEQ ID NO:45) is replaced by an AUG codon.

The nucleotide sequence of a PNPLA3 cDNA molecule encoding a PNPLA3 reference polypeptide having SEQ ID NO:38 is set forth in SEQ ID NO:48. The cDNA molecule encoding the PNPLA3 reference polypeptide having SEQ ID NO:38 comprises a cytosine at position 444. The cDNA molecule encoding the PNPLA3 reference polypeptide having SEQ ID NO:38 comprises an ATC codon at positions 442 to 444. The nucleotide sequence of a PNPLA3 cDNA molecule encoding a PNPLA3 reference polypeptide having SEQ ID NO:39 is set forth in SEQ ID NO:49. The cDNA molecule encoding the PNPLA3 reference polypeptide having SEQ ID NO:39 comprises a cytosine at position 432. The cDNA molecule encoding the PNPLA3 reference polypeptide having SEQ ID NO:39 comprises an ATC codon at positions 430 to 432.

The nucleotide sequence of a PNPLA3 cDNA molecule encoding PNPLA3 Ile148Met polypeptide is set forth in SEQ ID NO:50, wherein the cytosine at the position corresponding to position 444 of the PNPLA3 reference cDNA molecule (according to SEQ ID NO:48) is replaced with a guanine, and the ATC codon at positions corresponding to positions 442 to 444 of the PNPLA3 reference cDNA molecule (according to SEQ ID NO:48) is replaced by an ATG codon. The nucleotide sequence of a PNPLA3 cDNA molecule encoding PNPLA3 Ile144Met polypeptide is set forth in SEQ ID NO:51, wherein the cytosine at the position corresponding to position 432 of the PNPLA3 reference cDNA molecule (according to SEQ ID NO:49) is replaced with a guanine, and the ATC codon at positions corresponding to positions 430 to 432 of the PNPLA3 reference cDNA molecule (according to SEQ ID NO:49) is replaced by an ATG codon.

The present disclosure also provides methods of treating a subject with a CIDEB inhibitor and/or a PNPLA3 inhibitor and/or an HSD17B13 inhibitor, wherein the subject has a liver disease or is at risk of developing a liver disease, the methods comprising: determining whether the subject has a nucleic acid molecule encoding a PNPLA3 Ile148Met or Ile144Met polypeptide by: obtaining or having obtained a biological sample from the subject; and performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising the nucleic acid molecule encoding the PNPLA3 Ile148Met or Ile144Met polypeptide; and administering or continuing to administer the CIDEB inhibitor and/or a PNPLA3 inhibitor and/or an HSD17B13 inhibitor to a subject that is heterozygous or homozygous for the nucleic acid molecule encoding the PNPLA3 Ile148Met or Ile144Met polypeptide; wherein the presence of a genotype having the PNPLA3 nucleic acid molecule encoding the Ile148Met or Ile144Met polypeptide indicates the subject is a candidate for treatment with the CIDEB inhibitor and/or the HSD17B13 inhibitor and/or the PNPLA3 inhibitor. In some embodiments, the PNPLA3 nucleic acid molecule encodes PNPLA3 Ile148Met. In some embodiments, the PNPLA3 nucleic acid molecule encodes PNPLA3 Ile144Met. In some embodiments, the subject is also administered a therapeutic agent that treats or inhibits liver disease.

In some embodiments, the PNPLA3 nucleic acid molecule encoding the Ile148Met or Ile144Met polypeptide is: a genomic nucleic acid molecule having a nucleotide sequence comprising a guanine at a position corresponding to position 5109 according to SEQ ID NO:43; an mRNA molecule having a nucleotide sequence comprising a guanine at a position corresponding to position 444 according to SEQ ID NO:46, or a guanine at a position corresponding to position 432 according to SEQ ID NO:47; or a cDNA molecule produced from an mRNA molecule, wherein the cDNA molecule has a nucleotide sequence comprising a guanine at a position corresponding to position 444 according to SEQ ID NO: 50, or a guanine at a position corresponding to position 432 according to SEQ ID NO:51.

Methods of detection of any of the PNPLA3 genomic nucleic acid molecules, mRNA molecules, cDNA molecules, or polypeptides can be carried out by gene chip assays, bead assays, sequencing, or immunoassays.

In some embodiments, the sequence analysis comprises sequencing at least a portion of the nucleotide sequence of the PNPLA3 genomic nucleic acid molecule in the biological sample, wherein the sequenced portion comprises a position corresponding to position 5109 according to SEQ ID NO:43, or the complement thereof. In some embodiments, the sequence analysis comprises sequencing at least a portion of the nucleotide sequence of the PNPLA3 mRNA molecule in the biological sample, wherein the sequenced portion comprises a position corresponding to position 444 according to SEQ ID NO:46, or the complement thereof, or position 432 according to SEQ ID NO:47, or the complement thereof. In some embodiments, the sequence analysis comprises sequencing at least a portion of the nucleotide sequence of the PNPLA3 cDNA molecule in the biological sample, wherein the sequenced portion comprises a position corresponding to position 444 according to SEQ ID NO:50, or the complement thereof, or position 432 according to SEQ ID NO:51, or the complement thereof.

In some embodiments, the sequence analysis comprises: a) contacting the biological sample with a primer hybridizing to a portion of the nucleotide sequence of the PNPLA3 genomic nucleic acid molecule that is proximate to a position corresponding to position 5109 according to SEQ ID NO:43; b) extending the primer at least through the position of the nucleotide sequence of the PNPLA3 genomic nucleic acid molecule corresponding to position 5109 according to SEQ ID NO:43; and c) determining whether the extension product of the primer comprises a guanine at a position corresponding to position 5109 according to SEQ ID NO:43.

In some embodiments, the sequence analysis comprises: a) contacting the biological sample with a primer hybridizing to a portion of the nucleotide sequence of the PNPLA3 mRNA molecule that is proximate to a position corresponding to position 444 according to SEQ ID NO:46, or position 432 according to SEQ ID NO:47; b) extending the primer at least through the position of the nucleotide sequence of the PNPLA3 mRNA molecule corresponding to position 444 according to SEQ ID NO:46, or position 432 according to SEQ ID NO:47; and c) determining whether the extension product of the primer comprises a guanine at a position corresponding to position 444 according to SEQ ID NO:46, or a guanine at a position corresponding to position 432 according to SEQ ID NO:47.

In some embodiments, the sequence analysis comprises: a) contacting the biological sample with a primer hybridizing to a portion of the nucleotide sequence of the PNPLA3 cDNA molecule that is proximate to a position corresponding to position 444 according to SEQ ID NO:50, or position 432 according to SEQ ID NO:51; b) extending the primer at least through the position of the nucleotide sequence of the PNPLA3 cDNA molecule corresponding to position 444 according to SEQ ID NO:50, or position 432 according to SEQ ID NO:51; and c) determining whether the extension product of the primer comprises a guanine at a position corresponding to position 444 according to SEQ ID NO:50, or a guanine at a position corresponding to position 432 according to SEQ ID NO:51.

In some embodiments, the sequence analysis comprises sequencing the entire nucleic acid molecule.

In some embodiments, the sequence analysis comprises: a) amplifying at least a portion of the nucleic acid molecule that encodes the PNPLA3 polypeptide, wherein the portion comprises a guanine at a position corresponding to position 5109 according to SEQ ID NO:43, or the complement thereof; b) labeling the amplified nucleic acid molecule with a detectable label; c) contacting the labeled nucleic acid molecule with a support comprising an alteration-specific probe, wherein the alteration-specific probe comprises a nucleotide sequence which hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule comprising a guanine at a position corresponding to position 5109 according to SEQ ID NO:43, or the complement thereof; and d) detecting the detectable label.

In some embodiments, the sequence analysis comprises: a) amplifying at least a portion of the nucleic acid molecule that encodes the PNPLA3 polypeptide, wherein the portion comprises a guanine at a position corresponding to position 444 according to SEQ ID NO:46, or the complement thereof; or a guanine at a position corresponding to position 432 according to SEQ ID NO:47, or the complement thereof; b) labeling the amplified nucleic acid molecule with a detectable label; c) contacting the labeled nucleic acid molecule with a support comprising an alteration-specific probe, wherein the alteration-specific probe comprises a nucleotide sequence which hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule comprising a guanine at a position corresponding to position 444 according to SEQ ID NO:46, or the complement thereof; or a guanine at a position corresponding to position 432 according to SEQ ID NO:47, or the complement thereof; and d) detecting the detectable label.

In some embodiments, the sequence analysis comprises: a) amplifying at least a portion of the nucleic acid molecule that encodes the PNPLA3 polypeptide, wherein the portion comprises a guanine at a position corresponding to position 444 according to SEQ ID NO:50, or the complement thereof; or a guanine at a position corresponding to position 432 according to SEQ ID NO:51, or the complement thereof; b) labeling the amplified nucleic acid molecule with a detectable label; c) contacting the labeled nucleic acid molecule with a support comprising an alteration-specific probe, wherein the alteration-specific probe comprises a nucleotide sequence which hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule comprising a guanine at a position corresponding to position 444 according to SEQ ID NO:50, or the complement thereof; or a guanine at a position corresponding to position 432 according to SEQ ID NO:51, or the complement thereof; and d) detecting the detectable label. In some embodiments, the nucleic acid molecule in the sample is mRNA and the mRNA is reverse-transcribed into cDNA prior to the amplifying step.

In some embodiments, the sequence analysis comprises: contacting the nucleic acid molecule in the biological sample with an alteration-specific probe comprising a detectable label, wherein the alteration-specific probe comprises a nucleotide sequence which hybridizes under stringent conditions to the nucleotide sequence of the amplified nucleic acid molecule comprising a guanine at a position corresponding to position 5109 according to SEQ ID NO:43, or the complement thereof; and detecting the detectable label. In some embodiments, the sequence analysis comprises: contacting the nucleic acid molecule in the biological sample with an alteration-specific probe comprising a detectable label, wherein the alteration-specific probe comprises a nucleotide sequence which hybridizes under stringent conditions to the nucleotide sequence of the amplified nucleic acid molecule comprising a guanine at a position corresponding to position 444 according to SEQ ID NO:46, or the complement thereof; or a guanine at a position corresponding to position 432 according to SEQ ID NO:47, or the complement thereof; and detecting the detectable label. In some embodiments, the sequence analysis comprises: contacting the nucleic acid molecule in the biological sample with an alteration-specific probe comprising a detectable label, wherein the alteration-specific probe comprises a nucleotide sequence which hybridizes under stringent conditions to the nucleotide sequence of the amplified nucleic acid molecule comprising a guanine at a position corresponding to position 444 according to SEQ ID NO:50, or the complement thereof; or a guanine at a position corresponding to position 432 according to SEQ ID NO:51, or the complement thereof; and detecting the detectable label.

In some embodiments, the subject being treated with a CIDEB inhibitor, an HSD17B13 inhibitor, and/or a PNPLA3 inhibitor is heterozygous or homozygous for a nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide. In some embodiments, the subject being treated and having a nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide is administered the CIDEB inhibitor, the HSD17B13 inhibitor, and/or the PNPLA3 inhibitor to treat or prevent the complications of liver injury, liver fat accumulation, liver inflammation, fibrosis, liver cirrhosis or its comorbidities. In some embodiments, the CIDEB inhibitor, the HSD17B13 inhibitor, and/or the PNPLA3 inhibitor is administered to treat or prevent the complications of liver injury, liver fat accumulation, liver inflammation, fibrosis, liver cirrhosis or its comorbidities. In some embodiments, the CIDEB inhibitor, the HSD17B13 inhibitor, and/or the PNPLA3 inhibitor is administered to treat or prevent the complications of liver injury. In some embodiments, the CIDEB inhibitor, the HSD17B13 inhibitor, and/or the PNPLA3 inhibitor is administered to treat or prevent the complications of liver fat accumulation. In some embodiments, the CIDEB inhibitor, the HSD17B13 inhibitor, and/or the PNPLA3 inhibitor is administered to treat or prevent the complications of liver inflammation. In some embodiments, the CIDEB inhibitor, the HSD17B13 inhibitor, and/or the PNPLA3 inhibitor is administered to treat or prevent the complications of fibrosis. In some embodiments, the CIDEB inhibitor, the HSD17B13 inhibitor, and/or the PNPLA3 inhibitor is administered to treat or prevent the complications of liver cirrhosis or its comorbidities. In some embodiments, the methods further comprise genetic testing for the reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide to determine if the CIDEB inhibitor, the HSD17B13 inhibitor, and/or the PNPLA3 inhibitor has to be used or used in different doses or patterns of administration.

The present disclosure also provides methods of treating a subject having a liver disease or at risk of developing a liver disease and who is heterozygous or homozygous for a nucleic acid encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide, the methods comprising administering a CIDEB inhibitor, an HSD17B13 inhibitor, and/or a PNPLA3 inhibitor to the subject.

The amino acid sequences of two reference HSD17B13 polypeptides are set forth in SEQ ID NO:73 and SEQ ID NO:74. The reference HSD17B13 polypeptide having SEQ ID NO:73 is 264 amino acids in length, whereas the reference HSD17B13 polypeptide having SEQ ID NO:74 is 300 amino acids in length.

The nucleotide sequence of a genomic nucleic acid molecule encoding a reference HSD17B13 polypeptide is set forth in SEQ ID NO:52 (corresponding to ENSG00000170509.8 located at chr4:87,303,789-87,322,906 according to GRCh38/hg38 Human Genome Assembly).

The nucleotide sequence of an mRNA molecule encoding a reference HSD17B13 polypeptide is set forth in SEQ ID NO:53. The nucleotide sequence of another mRNA molecule encoding a reference HSD17B13 polypeptide is set forth in SEQ ID NO:54. The nucleotide sequence of another mRNA molecule encoding a reference HSD17B13 polypeptide is set forth in SEQ ID NO:55. The nucleotide sequence of another mRNA molecule encoding a reference HSD17B13 polypeptide is set forth in SEQ ID NO:56. The nucleotide sequence of another mRNA molecule encoding a reference HSD17B13 polypeptide is set forth in SEQ ID NO:57. The nucleotide sequence of another mRNA molecule encoding a reference HSD17B13 polypeptide is set forth in SEQ ID NO:58. The nucleotide sequence of another mRNA molecule encoding a reference HSD17B13 polypeptide is set forth in SEQ ID NO:59. The nucleotide sequence of another mRNA molecule encoding a reference HSD17B13 polypeptide is set forth in SEQ ID NO:60. The nucleotide sequence of another mRNA molecule encoding a reference HSD17B13 polypeptide is set forth in SEQ ID NO:61. The nucleotide sequence of another mRNA molecule encoding a reference HSD17B13 polypeptide is set forth in SEQ ID NO:62.

The nucleotide sequence of a cDNA molecule encoding a reference HSD17B13 polypeptide is set forth in SEQ ID NO:63. The nucleotide sequence of another cDNA molecule encoding a reference HSD17B13 polypeptide is set forth in SEQ ID NO:64. The nucleotide sequence of another cDNA molecule encoding a reference HSD17B13 polypeptide is set forth in SEQ ID NO:65. The nucleotide sequence of another cDNA molecule encoding a reference HSD17B13 polypeptide is set forth in SEQ ID NO:66. The nucleotide sequence of another cDNA molecule encoding a reference HSD17B13 polypeptide is set forth in SEQ ID NO:67. The nucleotide sequence of another cDNA molecule encoding a reference HSD17B13 polypeptide is set forth in SEQ ID NO:68. The nucleotide sequence of another cDNA molecule encoding a reference HSD17B13 polypeptide is set forth in SEQ ID NO:69. The nucleotide sequence of another cDNA molecule encoding a reference HSD17B13 polypeptide is set forth in SEQ ID NO:70. The nucleotide sequence of another cDNA molecule encoding a reference HSD17B13 polypeptide is set forth in SEQ ID NO:71. The nucleotide sequence of another cDNA molecule encoding a reference HSD17B13 polypeptide is set forth in SEQ ID NO:72.

The present disclosure also provides methods of treating a subject with a CIDEB inhibitor, an HSD17B13 inhibitor, and/or a PNPLA3 inhibitor, wherein the subject has a liver disease or is at risk of developing a liver disease, the methods comprising: determining whether the subject has a nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide by: obtaining or having obtained a biological sample from the subject; and performing or having performed an assay on the biological sample to determine whether the subject has: i) an HSD17B13 genomic nucleic acid molecule comprising SEQ ID NO:52, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:52 and encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide; ii) an HSD17B13 mRNA molecule comprising any one of SEQ ID NOs:53-62 or a nucleotide sequence having at least 90% sequence identity to any one of SEQ ID NOs:53-62 and encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide; or iii) an HSD17B13 cDNA molecule comprising any one of SEQ ID NOs:63-72 or a nucleotide sequence having at least 90% sequence identity to any one of SEQ ID NOs:63-72 and encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide, wherein the presence of a genotype having a nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide indicates the subject is a candidate for treatment with the CIDEB inhibitor, the HSD17B13 inhibitor, and/or the PNPLA3 inhibitor. In some embodiments, the subject is also administered a therapeutic agent that treats or inhibits liver disease.

In some embodiments, the nucleic acid molecule encoding the reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide is: a genomic nucleic acid molecule comprising the nucleotide sequence according to SEQ ID NO:52, or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:52 and encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide; an mRNA comprising the nucleotide sequence according to any one of SEQ ID NOs:53-62, or a nucleotide sequence having at least 90% sequence identity to any one of SEQ ID NOs:53-62 and encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide; or a cDNA comprising the nucleotide sequence according to any one of SEQ ID NOs:63-72 or a nucleotide sequence having at least 90% sequence identity to any one of SEQ ID NOs:63-72 and encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide.

Methods of detection of any of the HSD17B13 genomic nucleic acid molecules, mRNA molecules, cDNA molecules, or polypeptides can be carried out by gene chip assays, bead assays, sequencing, or immunoassays.

In some embodiments, the sequence analysis comprises sequencing at least a portion of the nucleotide sequence of the HSD17B13 genomic DNA, mRNA or cDNA produced from mRNA molecule in the biological sample.

In some embodiments, the sequence analysis comprises sequencing the entire nucleic acid molecule.

In some embodiments, the nucleic acid molecule is present within a cell obtained from the subject.

In some embodiments, the CIDEB inhibitor comprises an inhibitory nucleic acid molecule. In some embodiments, the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule, an siRNA, or an shRNA that hybridizes to a CIDEB nucleic acid molecule.

Examples of therapeutic agents that treat or inhibit liver disease include, but are not limited to: disulfiram, naltrexone, acamprosate, prednisone, azathioprine, penicillamine, trientine, deferoxamine, ciprofloxacin, norofloxacin, ceftriaxone, ofloxacin, amoxicillin-clavulanate, phytonadione, bumetanide, furosemide, hydrochlorothiazide, chlorothiazide, amiloride, triamterene, spironolactone, octreotide, atenolol, metoprolol, nadolol, propranolol, timolol, and carvedilol, or any combination thereof.

Additional examples of liver disease therapeutic agents (e.g., for use in chronic hepatitis C treatment) include, but are not limited to, ribavirin, paritaprevir, OLYSIO® (simeprevir), grazoprevir, ledipasvir, ombitasvir, elbasvir, DAKLINZA® (daclatasvir), dasabuvir, ritonavir, sofosbuvir, velpatasvir, voxilaprevir, glecaprevir, pibrentasvir, peginterferon alfa-2a, peginterferon alfa-2b, and interferon alfa-2b, or any combination thereof.

Additional examples of liver disease therapeutic agents (e.g., for use in nonalcoholic fatty liver disease) include, but are not limited to, weight loss inducing agents such as orlistat or sibutramine; insulin sensitizing agents such as thiazolidinediones (TZDs), metformin, and meglitinides; lipid lowering agents such as statins, fibrates, and omega-3 fatty acids; antioxidants such as, vitamin E, betaine, N-Acetyl-cysteine, lecithin, silymarin, and beta-carotene; anti TNF agents such as pentoxifylline; probiotics, such as VSL #3; and cytoprotective agents such as ursodeoxycholic acid (UDCA), or any combination thereof. Other suitable treatments include ACE inhibitors/ARBs, oligofructose, and Incretin analogs.

Additional examples of liver disease therapeutic agents (e.g., for use in NASH) include, but are not limited to, OCALIVA® (obeticholic acid), Selonsertib, Elafibranor, Cenicriviroc, GR_MD_02, MGL_3196, IMM124E, ARAMCHOL™ (arachidyl amido cholanoic acid), GS0976, Emricasan, Volixibat, NGM282, GS9674, Tropifexor, MN_001, LMB763, BI_1467335, MSDC_0602, PF_05221304, DF102, Saroglitazar, BMS986036, Lanifibranor, Semaglutide, Nitazoxanide, GRI_0621, EYP001, VK2809, Nalmefene, LIK066, MT_3995, Elobixibat, Namodenoson, Foralumab, SAR425899, Sotagliflozin, EDP_305, Isosabutate, Gemcabene, TERN_101, KBP_042, PF_06865571, DUR928, PF_06835919, NGM313, BMS_986171, Namacizumab, CER_209, ND_L02_s0201, RTU_1096, DRX_065, IONIS_DGAT2Rx, INT_767, NC_001, Seladepar, PXL770, TERN_201, NV556, AZD2693, SP_1373, VK0214, Hepastem, TGFTX4, RLBN1127, GKT_137831, RYI_018, CB4209-CB4211, and JH_0920, or any combination thereof.

Administration of the CIDEB inhibitor, PNPLA3 inhibitor, or HSD17B13 inhibitor, or any combination thereof, and/or therapeutic agents that treat or inhibit a liver disease can be repeated, for example, after one day, two days, three days, five days, one week, two weeks, three weeks, one month, five weeks, six weeks, seven weeks, eight weeks, two months, or three months. The repeated administration can be at the same dose or at a different dose. The administration can be repeated once, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times, or more. For example, according to certain dosage regimens a subject can receive therapy for a prolonged period of time such as, for example, 6 months, 1 year, or more.

Administration of the CIDEB inhibitor, PNPLA3 inhibitor, or HSD17B13 inhibitor, or any combination thereof, and/or therapeutic agents that treat or inhibit a liver disease can occur by any suitable route including, but not limited to, parenteral, intravenous, oral, subcutaneous, intra-arterial, intracranial, intrathecal, intraperitoneal, topical, intranasal, or intramuscular. Pharmaceutical compositions for administration are desirably sterile and substantially isotonic and manufactured under GMP conditions. Pharmaceutical compositions can be provided in unit dosage form (i.e., the dosage for a single administration). Pharmaceutical compositions can be formulated using one or more physiologically and pharmaceutically acceptable carriers, diluents, excipients or auxiliaries. The formulation depends on the route of administration chosen. The term “pharmaceutically acceptable” means that the carrier, diluent, excipient, or auxiliary is compatible with the other ingredients of the formulation and not substantially deleterious to the recipient thereof.

In any of the embodiments described herein, the subject can have or be at risk of developing any one or more of the liver diseases described herein. In some embodiments, the subject is CIDEB reference. In some embodiments, the subject is heterozygous for a CIDEB variant nucleic acid molecule. In some embodiments, the subject is homozygous for a CIDEB variant nucleic acid molecule.

The present disclosure also provides methods of treating a subject, wherein the subject is overweight, obese, has increased body mass index (BMI), has high liver fat percentage, or has high adiposity, the methods comprising administering to the subject a CIDEB inhibitor in an amount that is the same as or greater than a standard dosage amount, or a CIDEB inhibitor in combination with a PNPLA3 inhibitor and/or an HSD17B13 inhibitor. In some embodiments, the subject is obese. In some embodiments, the subject is overweight. In some embodiments, the subject has increased BMI. In some embodiments, the subject has high adiposity.

The terms “treat”, “treating”, and “treatment” and “prevent”, “preventing”, and “prevention” as used herein, refer to eliciting the desired biological response, such as a therapeutic and prophylactic effect, respectively. In some embodiments, a therapeutic effect comprises one or more of a decrease and/or reduction in a liver disease, a decrease and/or reduction in the severity of a liver disease, a decrease and/or reduction in symptoms and liver disease-related effects, delaying the onset of symptoms and liver disease-related effects, reducing the severity of symptoms of liver disease-related effects, reducing the number of symptoms and liver disease-related effects, reducing the latency of symptoms and liver disease-related effects, an amelioration of symptoms and liver disease-related effects, reducing secondary symptoms, reducing secondary infections, preventing relapse to a liver disease, decreasing the number or frequency of relapse episodes, increasing latency between symptomatic episodes, increasing time to sustained progression, speeding recovery, or increasing efficacy of or decreasing resistance to alternative therapeutics, and/or an increased survival time of the affected host animal, following administration of the agent or composition comprising the agent. A prophylactic effect may comprise a complete or partial avoidance and/or inhibition or a delay of liver disease development and/or progression (such as, for example, a complete or partial avoidance/inhibition or a delay), and an increased survival time of the affected host animal, following administration of a therapeutic protocol. Treatment of liver disease encompasses the treatment of subjects already diagnosed as having any form of liver disease at any clinical stage or manifestation, the delay of the onset or evolution or aggravation or deterioration of the symptoms or signs of liver disease, and/or preventing and/or reducing the severity of a liver disease.

The present disclosure also provides methods of identifying a subject having an increased risk of developing a liver disease. In some embodiments, the methods comprise determining or having determined in a biological sample obtained from the subject the presence or absence of a CIDEB variant nucleic acid molecule (such as a genomic nucleic acid molecule, mRNA molecule, and/or cDNA molecule). When the subject lacks a CIDEB variant nucleic acid molecule (i.e., the subject is genotypically categorized as a CIDEB reference), then the subject has an increased risk of developing a liver disease. When the subject has a CIDEB variant nucleic acid molecule (i.e., the subject is heterozygous or homozygous for a CIDEB variant nucleic acid molecule), then the subject has a decreased risk of developing a liver disease compared to a subject who is CIDEB reference.

Having a single copy of a CIDEB variant nucleic acid molecule is more protective of a subject from developing a liver disease than having no copies of a CIDEB variant nucleic acid molecule. Without intending to be limited to any particular theory or mechanism of action, it is believed that a single copy of a CIDEB variant nucleic acid molecule (i.e., heterozygous for a CIDEB variant nucleic acid molecule) is protective of a subject from developing a liver disease, and it is also believed that having two copies of a CIDEB variant nucleic acid molecule (i.e., homozygous for a CIDEB variant nucleic acid molecule) may be more protective of a subject from developing a liver disease, relative to a subject with a single copy. Thus, in some embodiments, a single copy of a CIDEB variant nucleic acid molecule may not be completely protective, but instead, may be partially or incompletely protective of a subject from developing a liver disease. While not desiring to be bound by any particular theory, there may be additional factors or molecules involved in the development of a liver disease that are still present in a subject having a single copy of a CIDEB variant nucleic acid molecule, thus resulting in less than complete protection from the development of a liver disease.

Determining whether a subject has a CIDEB variant nucleic acid molecule in a biological sample from a subject and/or determining whether a subject has a CIDEB variant nucleic acid molecule can be carried out by any of the methods described herein. In some embodiments, these methods can be carried out in vitro. In some embodiments, these methods can be carried out in situ. In some embodiments, these methods can be carried out in vivo. In any of these embodiments, the nucleic acid molecule can be present within a cell obtained from the subject.

The present disclosure also provides methods of identifying a subject having an increased risk of developing a liver disease, such as fatty liver disease, parenchymal liver disease, liver cirrhosis, and/or fibrosis, wherein the methods comprise determining or having determined the subject's gene burden of having one or more CIDEB variant genomic nucleic acid molecules described herein, one or more CIDEB variant mRNA molecules described herein, or one or more variant cDNA molecules described herein, and/or one or more CIDEB predicted loss-of-function polypeptides or missense polypeptides described herein. The greater the gene burden the subject has, the lower the risk of developing a liver disease. The lower the gene burden the subject has, the greater the risk of developing a liver disease.

In some embodiments, the subject's gene burden of having a plurality of (or all) CIDEB variant nucleic acid molecules represents a weighted sum of a plurality of genetic variants associated with protection against developing a liver disease. In some embodiments, the gene burden is calculated using at least about 2, at least about 3, at least about 4, at least about 5, at least about 10, at least about 20, at least about 30, at least about 40, at least about 50, at least about 60, at least about 70, at least about 80, at least about 100, at least about 120, at least about 150, at least about 200, at least about 250, at least about 300, at least about 400, at least about 500, or at least about 1,000 genetic variants associated with liver disease. In some embodiments, when the subject has a gene burden greater than a threshold score, the subject has a decreased risk of developing a liver disease. In some embodiments, when the subject has a gene burden below a threshold score, the subject has an increased risk of developing a liver disease.

In some embodiments, the gene burden is determined by consideration of one or more, or each, of the following variants: 14:24305635:A:AGTAG, 14:24305641:A:C, 14:24305650:G:A, 14:24305657:C:A, 14:24305662:G:T, 14:24305667:T:C, 14:24305671:C:A, 14:24305671:C:G, 14:24305701:A:T, 14:24305709:C:T, 14:24305718:A:G, 14:24305721:T:C, 14:24305728:G:GGCCTT, 14:24305743:T:C, 14:24305948:T:C, 14:24305966:C:T, 14:24305974:T:C, 14:24305980:TCA:T, 14:24305988:C:T, 14:24306014:C:T, 14:24306034:A:C, 14:24306041:C:G, 14:24306044:G:A, 14:24306047:G:A, 14:24306051:T:G, 14:24306064:T:C, 14:24306074:A:G, 14:24306077:G:C, 14:24306082:A:G, 14:24306083:T:A, 14:24306095:G:A, 14:24306122:A:G, 14:24306134:C:G, 14:24306373:C:G, 14:24306379:T:C, 14:24306382:G:A, 14:24306383:G:T, 14:24306426:T:G, 14:24306437:C:G, 14:24306439:G:C, 14:24306442:A:G, 14:24306444:A:G, 14:24306457:C:T, 14:24306463:C:T, 14:24306469:C:T, 14:24306480:A:G, 14:24306486:A:C, 14:24306504:A:G, 14:24306519:A:G, 14:24307382:G:C, 14:24307405:A:G, 14:24307417:A:T, 14:24307421:T:A, 14:24307441:C:A, 14:24307444:A:C, 14:24307444:A:G, 14:24307450:C:CGCTG, 14:24307461:TG:T, 14:24307469:AG:A, 14:24307474:C:T, 14:24307475:A:G, 14:24307833:G:C, 14:24307851:T:TAC, 14:24306426:T:C, 14:24307849:G:C, 14:24307448:G:T, 14:24305671:C:T, 14:24305663:C:T, 14:24305686:C:G, 14:24307829:A:C, 14:24307818:CTGAG:C, 14:24307856:C:T, 14:24306423:T:C, 14:24306061:AC:A, 14:24307390:C:T, 14:24306382:G:T, 14:24306373:C:T, 14:24305733:T:C, 14:24307858:T:C, 14:24306387:C:T, 14:24305637:T:C, 14:24306062:C:T, 14:24307853:C:G, 14:24307450:C:G, 14:24306052:TG:T, 14:24305673:G:A, 14:24306043:C:T, 14:24307834:G:A, 14:24306417:C:T, 14:24307451:G:A, 14:24307436:A:C, 14:24305953:ACTTT:A, 14:24306489:G:T, 14:24307441:C:T, 14:24306375:C:T, 14:24305657:C:G, 14:24306427:C:T, 14:24306524:C:T, 14:24307516:C:A, 14:24307840:G:C, 14:24307501:A:G, 14:24305968:A:C, 14:24305986:C:T, 14:24307441:C:G, 14:24307459:G:T, 14:24306017:T:A, 14:24307424:G:A, 14:24306072:G:T, 14:24307423:C:T, 14:24307450:C:T, 14:24306420:G:A, 14:24307454:G:A, 14:24305653:C:T, 14:24307442:G:A, 14:24306002:C:T, 14:24306076:C:T, 14:24305664:C:T, 14:24305961:TG:T, 14:24305706:A:G, 14:24305946:C:T, 14:24306455:G:C, 14:24307468:G:A, 14:24307825:A:C, 14:24306110:G:A, 14:24305710:C:T, 14:24307483:C:T, 14:24306459:A:G, 14:24305754:C:T, 14:24305650:G:C, 14:24305691:C:T, 14:24306508:G:C, 14:24306039:G:T, 14:24306139:T:C, 14:24306391:T:C, 14:24306373:C:A, 14:24307498:C:T, 14:24307415:G:A, 14:24306138:CTG:C, 14:24307453:T:C, 14:24305692:G:A, 14:24305683:C:G, 14:24307484:G:A, 14:24307385:C:T, 14:24306519:A:T, 14:24307839:A:C, 14:24305965:C:T, 14:24305988:CAT:C, 14:24306087:C:G, 14:24307439:C:T, 14:24307477:A:C, 14:24306436:G:T, 14:24306507:A:G, 14:24307397:C:T, 14:24307495:G:A, 14:24306034:A:T, 14:24306013:G:A, 14:24307381:A:G, 14:24306383:G:C, 14:24305638:A:G, 14:24307420:G:A, 14:24306020:C:T, 14:24306470:A:C, 14:24307435:C:T, 14:24306469:C:G, 14:24306451:C:T, 14:24306403:G:A, 14:24307515:C:G, 14:24307489:A:G, 14:24307414:C:T, 14:24306483:A:G, 14:24305755:G:A, 14:24305766:C:T, 14:24306064:T:G, 14:24307516:C:G, 14:24305766:C:G, 14:24306489:G:A, 14:24306097:T:C, 14:24305763:T:G, 14:24307447:G:A, 14:24307402:G:A, 14:24305972:C:G, 14:24306423:T:G, 14:24305974:T:TG, 14:24307411:T:C, 14:24306121:T:C, 14:24307516:C:T, 14:24306424:C:T, 14:24306039:G:C, 14:24307853:C:A, 14:24306388:A:G, 14:24305990:T:C, 14:24307822:G:GT, 14:24305640:G:A, 14:24307418:T:C, 14:24305758:G:C, 14:24306131:C:T, 14:24305953:A:G, 14:24305730:C:A, 14:24306418:A:G, 14:24306059:AC:A, 14:24307842:G:A, 14:24307837:T:G, 14:24306095:G:T, 14:24306109:C:T, 14:24307822:G:A, 14:24306077:G:A, 14:24307824:A:T, 14:24306080:C:T, 14:24305649:C:T, 14:24306433:G:GA, 14:24306420:G:C, 14:24305658:T:G, 14:24306472:C:T, 14:24307412:TC:T, 14:24306062:C:A, 14:24306044:G:C, 14:24306047:G:T, 14:24306126:CAG:C, 14:24306449:C:G, 14:24307391:G:A, or 14:24307857:A:C (according to GRCh38/hg38 human genome assembly coordinates).

In some embodiments, the gene burden may be divided into quintiles, e.g., top quintile, intermediate quintile, and bottom quintile, wherein the top quintile of gene burden corresponds to the lowest risk group and the bottom quintile of gene burden corresponds to the highest risk group.

In some embodiments, when a subject is identified as having an increased risk of developing a liver disease, the subject is further treated with a therapeutic agent that treats or inhibits liver disease and/or a CIDEB inhibitor, as described herein. For example, when the subject is CIDEB reference, and therefore has an increased risk of developing a liver disease, the subject can be administered a CIDEB inhibitor in a standard dosage amount. In some embodiments, such a subject is also administered a therapeutic agent that treats or inhibits a liver disease. In some embodiments, when the subject is heterozygous for a CIDEB variant nucleic acid molecule, the subject is administered the CIDEB inhibitor in a dosage amount that is the same as or less than a standard dosage amount, and can also be administered a therapeutic agent that treats or inhibits a liver disease. In some embodiments, the subject is CIDEB reference. In some embodiments, the subject is heterozygous for a CIDEB variant nucleic acid molecule.

The present disclosure also provides, in any of the methods described herein, the detection or determination of the presence of a CIDEB variant genomic nucleic acid molecule, a CIDEB variant mRNA molecule, and/or a CIDEB variant cDNA molecule produced from an mRNA molecule in a biological sample from a subject. It is understood that gene sequences within a population and mRNA molecules encoded by such genes can vary due to polymorphisms such as single-nucleotide polymorphisms. The sequences provided herein for the CIDEB variant nucleic acid molecules disclosed herein are only exemplary sequences. Other sequences for the CIDEB variant nucleic acid molecules are also possible.

The present disclosure also provides, in any of the methods described herein, the detection or determination of the presence of a genomic nucleic acid molecule encoding a PNPLA3 Ile148Met polypeptide or a PNPLA3 Ile144Met polypeptide, an mRNA molecule encoding a PNPLA3 Ile148Met polypeptide or a PNPLA3 Ile144Met polypeptide, a cDNA molecule encoding a PNPLA3 Ile148Met polypeptide or a PNPLA3 Ile144Met polypeptide, and/or a PNPLA3 Ile148Met polypeptide or a PNPLA3 Ile144Met polypeptide in a biological sample from the subject. It is understood that gene sequences within a population and mRNA molecules encoded by such genes can vary due to polymorphisms such as single-nucleotide polymorphisms. The sequences provided herein for the PNPLA3 variant nucleic acid molecules disclosed herein are only exemplary sequences. Other sequences for the PNPLA3 variant nucleic acid molecules are also possible. The detection or determination of the presence of PNPLA3 variant nucleic acid molecules is described in, for example, U.S. Pat. No. 10,961,583.

The present disclosure also provides, in any of the methods described herein, the detection or determination of the presence of a genomic nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide, an mRNA molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide, a cDNA molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide, and/or a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide in a biological sample from the subject. It is understood that gene sequences within a population and mRNA molecules encoded by such genes can vary due to polymorphisms such as single-nucleotide polymorphisms. The sequences provided herein for the HSD17B13 variant nucleic acid molecules disclosed herein are only exemplary sequences. Other sequences for the HSD17B13 nucleic acid molecules are also possible. The detection or determination of the presence of HSD17B13 nucleic acid molecules is described in, for example, U.S. Pat. No. 10,961,583.

The biological sample can be derived from any cell, tissue, or biological fluid from the subject. The sample may comprise any clinically relevant tissue, such as a bone marrow sample, a tumor biopsy, a fine needle aspirate, or a sample of bodily fluid, such as blood, gingival crevicular fluid, plasma, serum, lymph, ascitic fluid, cystic fluid, or urine. In some cases, the sample comprises a buccal swab. The sample used in the methods disclosed herein will vary based on the assay format, nature of the detection method, and the tissues, cells, or extracts that are used as the sample. A biological sample can be processed differently depending on the assay being employed. For example, when detecting any of the nucleic acid molecules, preliminary processing designed to isolate or enrich the sample for the genomic DNA can be employed. A variety of known techniques may be used for this purpose. When detecting the presence of or level of any CIDEB, PNPLA3, and/or HSD17B13 mRNA molecule, different techniques can be used enrich the biological sample with mRNA. Various methods to detect the presence or level of a mRNA or the presence of a particular variant genomic DNA locus can be used.

In some embodiments, detecting a CIDEB variant nucleic acid molecule in a subject comprises assaying or performing a sequence analysis on a biological sample obtained from the subject to determine whether a CIDEB genomic nucleic acid molecule, a CIDEB mRNA molecule, or a CIDEB cDNA molecule produced from an mRNA molecule in the biological sample is a CIDEB variant nucleic acid molecule.

In some embodiments, the methods of detecting the presence or absence of a CIDEB variant nucleic acid molecule (such as, for example, a genomic nucleic acid molecule, an mRNA molecule, and/or a cDNA molecule) in a subject, comprise performing an assay on a biological sample obtained from the subject, which assay determines whether a nucleic acid molecule in the biological sample comprises a particular nucleotide sequence.

In some embodiments, detecting a nucleic acid molecule encoding a PNPLA3 Ile148Met or Ile144Met polypeptide in a subject comprises assaying or performing a sequence analysis on a biological sample obtained from the subject to determine whether a PNPLA3 genomic nucleic acid molecule, a PNPLA3 mRNA molecule, or a PNPLA3 cDNA molecule produced from an mRNA molecule in the biological sample encodes an Ile148Met or Ile144Met polypeptide.

In some embodiments, the methods of detecting the presence or absence of a nucleic acid molecule encoding a PNPLA3 Ile148Met or Ile144Met polypeptide (such as, for example, a genomic nucleic acid molecule, an mRNA molecule, and/or a cDNA molecule) in a subject, comprise performing an assay on a biological sample obtained from the subject, which assay determines whether a nucleic acid molecule in the biological sample comprises a particular nucleotide sequence.

In some embodiments, detecting a nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide comprises assaying or performing a sequence analysis on a biological sample obtained from the subject to determine whether a HSD17B13 genomic nucleic acid molecule, a HSD17B13 mRNA molecule, or a HSD17B13 cDNA molecule produced from an mRNA molecule in the biological sample encodes a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide.

In some embodiments, the methods of detecting the presence or absence of a nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide (such as, for example, a genomic nucleic acid molecule, an mRNA molecule, and/or a cDNA molecule) in a subject, comprise performing an assay on a biological sample obtained from the subject, which assay determines whether a nucleic acid molecule in the biological sample comprises a particular nucleotide sequence.

In some embodiments, the biological sample comprises a cell or cell lysate. Such methods can further comprise, for example, obtaining a biological sample from the subject comprising a CIDEB, PNPLA3, and/or HSD17B13 genomic nucleic acid molecule or mRNA molecule, and if mRNA, optionally reverse transcribing the mRNA into cDNA. Such assays can comprise, for example determining the identity of these positions of the particular, CIDEB, PNPLA3, and/or HSD17B13 nucleic acid molecule. In some embodiments, the method is an in vitro method.

In some embodiments, the determining step, detecting step, or sequence analysis comprises sequencing at least a portion of the nucleotide sequence of the CIDEB, PNPLA3, and/or HSD17B13 genomic nucleic acid molecule, the CIDEB, PNPLA3, and/or HSD17B13 mRNA molecule, or the CIDEB, PNPLA3, and/or HSD17B13 cDNA molecule produced from the mRNA molecule in the biological sample, wherein the sequenced portion comprises one or more variations that cause a loss-of-function or missense (partial or complete) or are predicted to cause a loss-of-function or missense (partial or complete), such as any one or more of the CIDEB, PNPLA3, and/or HSD17B13 nucleic acid molecules described herein.

In any of the methods described herein, the determining step, detecting step, or sequence analysis comprises sequencing at least a portion of the nucleotide sequence of the CIDEB or PNPLA3 nucleic acid molecule in the biological sample, wherein the sequenced portion comprises a position corresponding to a variant nucleic acid molecule position, wherein when a variant nucleotide at the variant nucleic acid molecule position is detected, the CIDEB or PNPLA3 nucleic acid molecule in the biological sample is a CIDEB or PNPLA3 variant nucleic acid molecule.

In some embodiments, the determining step, detecting step, or sequence analysis comprises: a) contacting the biological sample with a primer hybridizing to a portion of the nucleotide sequence of the CIDEB nucleic acid molecule that is proximate to a variant nucleic acid molecule position; b) extending the primer at least through the variant nucleic acid molecule position; and c) determining whether the extension product of the primer comprises a variant nucleotide at the variant nucleic acid molecule position.

In some embodiments, the assay comprises sequencing the entire nucleic acid molecule. In some embodiments, only a CIDEB genomic nucleic acid molecule is analyzed. In some embodiments, only a CIDEB mRNA is analyzed. In some embodiments, only a CIDEB cDNA obtained from CIDEB mRNA is analyzed.

In some embodiments, the determining step, detecting step, or sequence analysis comprises: a) amplifying at least a portion of the CIDEB nucleic acid molecule that encodes the CIDEB polypeptide, wherein the portion comprises a variant nucleic acid molecule position; b) labeling the amplified nucleic acid molecule with a detectable label; c) contacting the labeled nucleic acid molecule with a support comprising an alteration-specific probe, wherein the alteration-specific probe comprises a nucleotide sequence which hybridizes under stringent conditions to the variant nucleic acid molecule position; and d) detecting the detectable label.

In any of the methods described herein, the determining step, detecting step, or sequence analysis comprises sequencing at least a portion of the nucleotide sequence of the nucleotide sequence of the PNPLA3 genomic nucleic acid molecule in the biological sample, wherein the sequenced portion comprises a position corresponding to position 5109 according to SEQ ID NO:43 (i.e., the variant nucleic acid molecule position), or the complement thereof. In some embodiments, the sequence analysis comprises sequencing at least a portion of the nucleotide sequence of the PNPLA3 mRNA molecule in the biological sample, wherein the sequenced portion comprises a position corresponding to position 444 according to SEQ ID NO:46 (i.e., the variant nucleic acid molecule position), or the complement thereof; or position 432 according to SEQ ID NO:47 (i.e., the variant nucleic acid molecule position), or the complement thereof. In some embodiments, the sequence analysis comprises sequencing at least a portion of the nucleotide sequence of the PNPLA3 cDNA molecule in the biological sample, wherein the sequenced portion comprises a position corresponding to position 444 according to SEQ ID NO:50 (i.e., the variant nucleic acid molecule position), or the complement thereof; or position 432 according to SEQ ID NO:51 (i.e., the variant nucleic acid molecule position), or the complement thereof.

In some embodiments, the sequence analysis comprises: a) contacting the biological sample with a primer hybridizing to a portion of the nucleotide sequence of the PNPLA3 genomic nucleic acid molecule that is proximate to a position corresponding to position 5109 according to SEQ ID NO:43; b) extending the primer at least through the position of the nucleotide sequence of the PNPLA3 genomic nucleic acid molecule corresponding to position 5109 according to SEQ ID NO:43; and c) determining whether the extension product of the primer comprises a guanine at a position corresponding to position 5109 according to SEQ ID NO:43.

In some embodiments, the sequence analysis comprises: a) contacting the biological sample with a primer hybridizing to a portion of the nucleotide sequence of the PNPLA3 mRNA molecule that is proximate to a position corresponding to position 444 according to SEQ ID NO:46, or position 432 according to SEQ ID NO:47; b) extending the primer at least through the position of the nucleotide sequence of the PNPLA3 mRNA molecule corresponding to position 444 according to SEQ ID NO:46, or position 432 according to SEQ ID NO:47; and c) determining whether the extension product of the primer comprises a guanine at a position corresponding to position 444 according to SEQ ID NO:46, or a guanine at a position corresponding to position 432 according to SEQ ID NO:47.

In some embodiments, the sequence analysis comprises: a) contacting the biological sample with a primer hybridizing to a portion of the nucleotide sequence of the PNPLA3 cDNA molecule that is proximate to a position corresponding to position 444 according to SEQ ID NO:50, or position 432 according to SEQ ID NO:51; b) extending the primer at least through the position of the nucleotide sequence of the PNPLA3 cDNA molecule corresponding to position 444 according to SEQ ID NO:50, or position 432 according to SEQ ID NO:51; and c) determining whether the extension product of the primer comprises a guanine at a position corresponding to position 444 according to SEQ ID NO:50, or a guanine at a position corresponding to position 432 according to SEQ ID NO:51.

In some embodiments, the assay comprises sequencing the entire nucleic acid molecule. In some embodiments, only a PNPLA3 genomic nucleic acid molecule is analyzed. In some embodiments, only a PNPLA3 mRNA is analyzed. In some embodiments, only a PNPLA3 cDNA obtained from PNPLA3 mRNA is analyzed.

In some embodiments, the sequence analysis comprises: a) amplifying at least a portion of the nucleic acid molecule that encodes the PNPLA3 polypeptide, wherein the portion comprises a guanine at a position corresponding to position 5109 according to SEQ ID NO:43, or the complement thereof; b) labeling the amplified nucleic acid molecule with a detectable label; c) contacting the labeled nucleic acid molecule with a support comprising an alteration-specific probe, wherein the alteration-specific probe comprises a nucleotide sequence which hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule comprising a guanine at a position corresponding to position 5109 according to SEQ ID NO:43, or the complement thereof; and d) detecting the detectable label.

In some embodiments, the sequence analysis comprises: a) amplifying at least a portion of the nucleic acid molecule that encodes the PNPLA3 polypeptide, wherein the portion comprises a guanine at a position corresponding to position 444 according to SEQ ID NO:46, or the complement thereof; or a guanine at a position corresponding to position 432 according to SEQ ID NO:47, or the complement thereof; b) labeling the amplified nucleic acid molecule with a detectable label; c) contacting the labeled nucleic acid molecule with a support comprising an alteration-specific probe, wherein the alteration-specific probe comprises a nucleotide sequence which hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule comprising a guanine at a position corresponding to position 444 according to SEQ ID NO:46, or the complement thereof; or a guanine at a position corresponding to position 432 according to SEQ ID NO:47, or the complement thereof; and d) detecting the detectable label.

In some embodiments, the sequence analysis comprises: a) amplifying at least a portion of the nucleic acid molecule that encodes the PNPLA3 polypeptide, wherein the portion comprises a guanine at a position corresponding to position 444 according to SEQ ID NO:50, or the complement thereof; or a guanine at a position corresponding to position 432 according to SEQ ID NO:51, or the complement thereof; b) labeling the amplified nucleic acid molecule with a detectable label; c) contacting the labeled nucleic acid molecule with a support comprising an alteration-specific probe, wherein the alteration-specific probe comprises a nucleotide sequence which hybridizes under stringent conditions to the nucleic acid sequence of the amplified nucleic acid molecule comprising a guanine at a position corresponding to position 444 according to SEQ ID NO:50, or the complement thereof; or a guanine at a position corresponding to position 432 according to SEQ ID NO:51, or the complement thereof; and d) detecting the detectable label.

In any of the methods described herein, the determining step, detecting step, or sequence analysis comprises obtaining or having obtained a biological sample from the subject; and performing or having performed an assay on the biological sample to determine whether the subject has: i) an HSD17B13 genomic DNA comprising SEQ ID NO:52; or a nucleotide sequence having at least 90% sequence identity to SEQ ID NO:52 and encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide; ii) an HSD17B13 mRNA comprising any one of SEQ ID NOs:53-62, or a nucleotide sequence having at least 90% sequence identity to any one of SEQ ID NOs:53-62 and encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide; or iii) an HSD17B13 cDNA comprising any one of SEQ ID NOs:63-72, or a nucleotide sequence having at least 90% sequence identity to any one SEQ ID NOs:63-72 and encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide.

In some embodiments, the sequence analysis comprises sequencing at least a portion of the nucleotide sequence of the HSD17B13 genomic DNA, mRNA or cDNA produced from mRNA molecule in the biological sample.

In some embodiments, the nucleic acid molecule is mRNA and the determining step further comprises reverse-transcribing the mRNA into a cDNA prior to the amplifying step.

In some embodiments, the determining step, detecting step, or sequence analysis comprises: contacting the nucleic acid molecule in the biological sample with an alteration-specific probe comprising a detectable label, wherein the alteration-specific probe comprises a nucleotide sequence which hybridizes under stringent conditions to a variant nucleic acid molecule position; and detecting the detectable label.

The alteration-specific probes or alteration-specific primers described herein comprise a nucleic acid sequence which is complementary to and/or hybridizes, or specifically hybridizes, to a CIDEB variant nucleic acid molecule, or the complement thereof. In some embodiments, the alteration-specific probes or alteration-specific primers comprise or consist of at least about 1, at least about 5, at least about 8, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, or at least about 50 nucleotides. In some embodiments, the alteration-specific probes or alteration-specific primers comprise or consist of at least 15 nucleotides. In some embodiments, the alteration-specific probes or alteration-specific primers comprise or consist of at least 15 nucleotides to at least about 35 nucleotides. In some embodiments, alteration-specific probes or alteration-specific primers hybridize to CIDEB variant genomic nucleic acid molecules, CIDEB variant mRNA molecules, and/or CIDEB variant cDNA molecules under stringent conditions.

The alteration-specific probes or alteration-specific primers described herein comprise a nucleic acid sequence which is complementary to and/or hybridizes, or specifically hybridizes, to a nucleic acid molecule encoding a PNPLA3 Ile148Met or Ile144Met polypeptide, or the complement thereof. In some embodiments, the alteration-specific probes or alteration-specific primers comprise or consist of at least about 1, at least about 5, at least about 8, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, or at least about 50 nucleotides. In some embodiments, the alteration-specific probes or alteration-specific primers comprise or consist of at least 15 nucleotides. In some embodiments, the alteration-specific probes or alteration-specific primers comprise or consist of at least 15 nucleotides to at least about 35 nucleotides. In some embodiments, alteration-specific probes or alteration-specific primers hybridize to genomic nucleic acid molecules encoding a PNPLA3 Ile148Met or Ile144Met polypeptide, mRNA molecules encoding a PNPLA3 Ile148Met or Ile144Met polypeptide, and/or cDNA molecules encoding a PNPLA3 Ile148Met or Ile144Met polypeptide under stringent conditions.

Alteration-specific polymerase chain reaction techniques can be used to detect mutations such as SNPs in a nucleic acid sequence. Alteration-specific primers can be used because the DNA polymerase will not extend when a mismatch with the template is present.

In some embodiments, the nucleic acid molecule in the sample is mRNA and the mRNA is reverse-transcribed into a cDNA prior to the amplifying step. In some embodiments, the nucleic acid molecule is present within a cell obtained from the subject.

In some embodiments, the assay comprises contacting the biological sample with a primer or probe, such as an alteration-specific primer or alteration-specific probe, that specifically hybridizes to a CIDEB variant genomic sequence, variant mRNA sequence, or variant cDNA sequence and not the corresponding CIDEB reference sequence under stringent conditions, and determining whether hybridization has occurred.

In some embodiments, the assay comprises contacting the biological sample with a primer or probe, such as an alteration-specific primer or alteration-specific probe, that specifically hybridizes to genomic nucleic acid molecules encoding a PNPLA3 Ile148Met or Ile144Met polypeptide, mRNA molecules encoding a PNPLA3 Ile148Met or Ile144Met polypeptide, and/or cDNA molecules encoding a PNPLA3 Ile148Met or Ile144Met polypeptide under stringent conditions, and determining whether hybridization has occurred.

In some embodiments, the assay comprises RNA sequencing (RNA-Seq). In some embodiments, the assays also comprise reverse transcribing mRNA into cDNA, such as by the reverse transcriptase polymerase chain reaction (RT-PCR).

In some embodiments, the methods utilize probes and primers of sufficient nucleotide length to bind to the target nucleotide sequence and specifically detect and/or identify a polynucleotide comprising a CIDEB variant genomic nucleic acid molecule, a variant mRNA molecule, or a variant cDNA molecule, and/or a nucleic acid molecule encoding a PNPLA3 Ile148Met or Ile144Met polypeptide, an mRNA molecule encoding a PNPLA3 Ile148Met or Ile144Met polypeptide, and/or a cDNA molecule encoding a PNPLA3 Ile148Met or Ile144Met polypeptide. The hybridization conditions or reaction conditions can be determined by the operator to achieve this result. The nucleotide length may be any length that is sufficient for use in a detection method of choice, including any assay described or exemplified herein. Such probes and primers can hybridize specifically to a target nucleotide sequence under high stringency hybridization conditions. Probes and primers may have complete nucleotide sequence identity of contiguous nucleotides within the target nucleotide sequence, although probes differing from the target nucleotide sequence and that retain the ability to specifically detect and/or identify a target nucleotide sequence may be designed by conventional methods. Probes and primers can have about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100% sequence identity or complementarity with the nucleotide sequence of the target nucleic acid molecule.

Illustrative examples of nucleic acid sequencing techniques include, but are not limited to, chain terminator (Sanger) sequencing and dye terminator sequencing. Other methods involve nucleic acid hybridization methods other than sequencing, including using labeled primers or probes directed against purified DNA, amplified DNA, and fixed cell preparations (fluorescence in situ hybridization (FISH)). In some methods, a target nucleic acid molecule may be amplified prior to or simultaneous with detection. Illustrative examples of nucleic acid amplification techniques include, but are not limited to, polymerase chain reaction (PCR), ligase chain reaction (LCR), strand displacement amplification (SDA), and nucleic acid sequence based amplification (NASBA). Other methods include, but are not limited to, ligase chain reaction, strand displacement amplification, and thermophilic SDA (tSDA).

In hybridization techniques, stringent conditions can be employed such that a probe or primer will specifically hybridize to its target. In some embodiments, a polynucleotide primer or probe under stringent conditions will hybridize to its target sequence to a detectably greater degree than to other non-target sequences, such as, at least 2-fold, at least 3-fold, at least 4-fold, or more over background, including over 10-fold over background. Stringent conditions are sequence-dependent and will be different in different circumstances.

Appropriate stringency conditions which promote DNA hybridization, for example, 6× sodium chloride/sodium citrate (SSC) at about 45° C., followed by a wash of 2×SSC at 50° C., are known or can be found in Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6. Typically, stringent conditions for hybridization and detection will be those in which the salt concentration is less than about 1.5 M Na⁺ ion, typically about 0.01 to 1.0 M Na⁺ ion concentration (or other salts) at pH 7.0 to 8.3 and the temperature is at least about 30° C. for short probes (such as, for example, 10 to 50 nucleotides) and at least about 60° C. for longer probes (such as, for example, greater than 50 nucleotides). Stringent conditions may also be achieved with the addition of destabilizing agents such as formamide. Optionally, wash buffers may comprise about 0.1% to about 1% SDS. Duration of hybridization is generally less than about 24 hours, usually about 4 to about 12 hours. The duration of the wash time will be at least a length of time sufficient to reach equilibrium.

In some embodiments, detecting the presence of a predicted loss-of-function polypeptide or missense polypeptide comprises performing an assay on a sample obtained from a subject to determine whether a CIDEB polypeptide in the subject contains one or more variations that causes the polypeptide to have a loss-of-function (partial or complete) or predicted loss-of-function (partial or complete) or missense variant. In some embodiments, the assay comprises sequencing at least a portion of the CIDEB polypeptide that comprises a variant position. In some embodiments, the detecting step comprises sequencing the entire polypeptide. Identification of a variant amino acid at the variant position of the CIDEB polypeptide indicates that the CIDEB polypeptide is a predicted loss-of-function or missense CIDEB polypeptide. In some embodiments, the assay comprises an immunoassay for detecting the presence of a polypeptide that comprises a variant. Detection of a variant amino acid at the variant position of the CIDEB polypeptide indicates that the CIDEB polypeptide is a CIDEB predicted loss-of-function or missense polypeptide.

In some embodiments, detecting the presence of a PNPLA3 Ile148Met or Ile144Met polypeptide comprises performing an assay on a sample obtained from a subject to determine whether a PNPLA3 polypeptide in the subject contains the Ile148Met or Ile144Met variation. In some embodiments, the assay comprises sequencing at least a portion of the PNPLA3 polypeptide that comprises a variant position. In some embodiments, the detecting step comprises sequencing the entire polypeptide. In some embodiments, the assay comprises an immunoassay for detecting the presence of a polypeptide that comprises a variant.

In some embodiments, isolated nucleic acid molecules hybridize to CIDEB variant nucleic acid molecules, nucleic acid molecules encoding a PNPLA3 Ile148Met or Ile144Met polypeptide, or nucleic acid molecules encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide (such as genomic nucleic acid molecules, mRNA molecules, and/or cDNA molecules) under stringent conditions. Such nucleic acid molecules can be used, for example, as probes, primers, alteration-specific probes, or alteration-specific primers as described or exemplified herein, and include, without limitation primers, probes, antisense RNAs, shRNAs, and siRNAs, each of which is described in more detail elsewhere herein, and can be used in any of the methods described herein.

In some embodiments, the isolated nucleic acid molecules hybridize to at least about 15 contiguous nucleotides of a nucleic acid molecule that is at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to CIDEB variant genomic nucleic acid molecules, CIDEB variant mRNA molecules, and/or CIDEB variant cDNA molecules.

In some embodiments, the isolated nucleic acid molecules hybridize to at least about 15 contiguous nucleotides of a nucleic acid molecule that is at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to PNPLA3 genomic nucleic acid molecules encoding a PNPLA3 Ile148Met or Ile144Met polypeptide, PNPLA3 mRNA molecules encoding a PNPLA3 Ile148Met or Ile144Met polypeptide, and/or PNPLA3 cDNA molecules encoding a PNPLA3 Ile148Met or Ile144Met polypeptide.

In some embodiments, the isolated nucleic acid molecules hybridize to at least about 15 contiguous nucleotides of a nucleic acid molecule that is at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to HSD17B13 genomic nucleic acid molecules encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide, HSD17B13 mRNA molecules encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide, and/or HSD17B13 cDNA molecules encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide. In some embodiments, the isolated nucleic acid molecules consist of or comprise from about 15 to about 100 nucleotides, or from about 15 to about 35 nucleotides. In some embodiments, the isolated nucleic acid molecules consist of or comprise from about 15 to about 100 nucleotides. In some embodiments, the isolated nucleic acid molecules consist of or comprise from about 15 to about 35 nucleotides.

In some embodiments, the alteration-specific probes and alteration-specific primers comprise DNA. In some embodiments, the alteration-specific probes and alteration-specific primers comprise RNA.

In some embodiments, the probes and primers described herein (including alteration-specific probes and alteration-specific primers) have a nucleotide sequence that specifically hybridizes to any of the nucleic acid molecules disclosed herein, or the complement thereof. In some embodiments, the probes and primers specifically hybridize to any of the nucleic acid molecules disclosed herein under stringent conditions.

In some embodiments, the primers, including alteration-specific primers, can be used in second generation sequencing or high throughput sequencing. In some instances, the primers, including alteration-specific primers, can be modified. In particular, the primers can comprise various modifications that are used at different steps of, for example, Massive Parallel Signature Sequencing (MPSS), Polony sequencing, and 454 Pyrosequencing. Modified primers can be used at several steps of the process, including biotinylated primers in the cloning step and fluorescently labeled primers used at the bead loading step and detection step. Polony sequencing is generally performed using a paired-end tags library wherein each molecule of DNA template is about 135 bp in length. Biotinylated primers are used at the bead loading step and emulsion PCR. Fluorescently labeled degenerate nonamer oligonucleotides are used at the detection step. An adaptor can contain a 5′-biotin tag for immobilization of the DNA library onto streptavidin-coated beads.

The probes and primers described herein can also be used to detect a nucleotide variation within any of the CIDEB variant genomic nucleic acid molecules, CIDEB variant mRNA molecules, and/or CIDEB variant cDNA molecules disclosed herein. The primers described herein can be used to amplify CIDEB variant genomic nucleic acid molecules, CIDEB variant mRNA molecules, or CIDEB variant cDNA molecules, or a fragment thereof.

In some embodiments, the probes (such as, for example, an alteration-specific probe) comprise a label. In some embodiments, the label is a fluorescent label, a radiolabel, or biotin.

The present disclosure also provides supports comprising a substrate to which any one or more of the probes disclosed herein is attached. Solid supports are solid-state substrates or supports with which molecules, such as any of the probes disclosed herein, can be associated. A form of solid support is an array. Another form of solid support is an array detector. An array detector is a solid support to which multiple different probes have been coupled in an array, grid, or other organized pattern. A form for a solid-state substrate is a microtiter dish, such as a standard 96-well type. In some embodiments, a multiwell glass slide can be employed that normally contains one array per well.

The present disclosure also provides therapeutic compositions that treat or inhibit a liver disease for use in the treatment of a liver disease in a subject having one or more CIDEB variant nucleic acid molecules comprising: 14:24305635:A:AGTAG, 14:24305641:A:C, 14:24305650:G:A, 14:24305657:C:A, 14:24305662:G:T, 14:24305667:T:C, 14:24305671:C:A, 14:24305671:C:G, 14:24305701:A:T, 14:24305709:C:T, 14:24305718:A:G, 14:24305721:T:C, 14:24305728:G:GGCCTT, 14:24305743:T:C, 14:24305948:T:C, 14:24305966:C:T, 14:24305974:T:C, 14:24305980:TCA:T, 14:24305988:C:T, 14:24306014:C:T, 14:24306034:A:C, 14:24306041:C:G, 14:24306044:G:A, 14:24306047:G:A, 14:24306051:T:G, 14:24306064:T:C, 14:24306074:A:G, 14:24306077:G:C, 14:24306082:A:G, 14:24306083:T:A, 14:24306095:G:A, 14:24306122:A:G, 14:24306134:C:G, 14:24306373:C:G, 14:24306379:T:C, 14:24306382:G:A, 14:24306383:G:T, 14:24306426:T:G, 14:24306437:C:G, 14:24306439:G:C, 14:24306442:A:G, 14:24306444:A:G, 14:24306457:C:T, 14:24306463:C:T, 14:24306469:C:T, 14:24306480:A:G, 14:24306486:A:C, 14:24306504:A:G, 14:24306519:A:G, 14:24307382:G:C, 14:24307405:A:G, 14:24307417:A:T, 14:24307421:T:A, 14:24307441:C:A, 14:24307444:A:C, 14:24307444:A:G, 14:24307450:C:CGCTG, 14:24307461:TG:T, 14:24307469:AG:A, 14:24307474:C:T, 14:24307475:A:G, 14:24307833:G:C, 14:24307851:T:TAC, 14:24306426:T:C, 14:24307849:G:C, 14:24307448:G:T, 14:24305671:C:T, 14:24305663:C:T, 14:24305686:C:G, 14:24307829:A:C, 14:24307818:CTGAG:C, 14:24307856:C:T, 14:24306423:T:C, 14:24306061:AC:A, 14:24307390:C:T, 14:24306382:G:T, 14:24306373:C:T, 14:24305733:T:C, 14:24307858:T:C, 14:24306387:C:T, 14:24305637:T:C, 14:24306062:C:T, 14:24307853:C:G, 14:24307450:C:G, 14:24306052:TG:T, 14:24305673:G:A, 14:24306043:C:T, 14:24307834:G:A, 14:24306417:C:T, 14:24307451:G:A, 14:24307436:A:C, 14:24305953:ACTTT:A, 14:24306489:G:T, 14:24307441:C:T, 14:24306375:C:T, 14:24305657:C:G, 14:24306427:C:T, 14:24306524:C:T, 14:24307516:C:A, 14:24307840:G:C, 14:24307501:A:G, 14:24305968:A:C, 14:24305986:C:T, 14:24307441:C:G, 14:24307459:G:T, 14:24306017:T:A, 14:24307424:G:A, 14:24306072:G:T, 14:24307423:C:T, 14:24307450:C:T, 14:24306420:G:A, 14:24307454:G:A, 14:24305653:C:T, 14:24307442:G:A, 14:24306002:C:T, 14:24306076:C:T, 14:24305664:C:T, 14:24305961:TG:T, 14:24305706:A:G, 14:24305946:C:T, 14:24306455:G:C, 14:24307468:G:A, 14:24307825:A:C, 14:24306110:G:A, 14:24305710:C:T, 14:24307483:C:T, 14:24306459:A:G, 14:24305754:C:T, 14:24305650:G:C, 14:24305691:C:T, 14:24306508:G:C, 14:24306039:G:T, 14:24306139:T:C, 14:24306391:T:C, 14:24306373:C:A, 14:24307498:C:T, 14:24307415:G:A, 14:24306138:CTG:C, 14:24307453:T:C, 14:24305692:G:A, 14:24305683:C:G, 14:24307484:G:A, 14:24307385:C:T, 14:24306519:A:T, 14:24307839:A:C, 14:24305965:C:T, 14:24305988:CAT:C, 14:24306087:C:G, 14:24307439:C:T, 14:24307477:A:C, 14:24306436:G:T, 14:24306507:A:G, 14:24307397:C:T, 14:24307495:G:A, 14:24306034:A:T, 14:24306013:G:A, 14:24307381:A:G, 14:24306383:G:C, 14:24305638:A:G, 14:24307420:G:A, 14:24306020:C:T, 14:24306470:A:C, 14:24307435:C:T, 14:24306469:C:G, 14:24306451:C:T, 14:24306403:G:A, 14:24307515:C:G, 14:24307489:A:G, 14:24307414:C:T, 14:24306483:A:G, 14:24305755:G:A, 14:24305766:C:T, 14:24306064:T:G, 14:24307516:C:G, 14:24305766:C:G, 14:24306489:G:A, 14:24306097:T:C, 14:24305763:T:G, 14:24307447:G:A, 14:24307402:G:A, 14:24305972:C:G, 14:24306423:T:G, 14:24305974:T:TG, 14:24307411:T:C, 14:24306121:T:C, 14:24307516:C:T, 14:24306424:C:T, 14:24306039:G:C, 14:24307853:C:A, 14:24306388:A:G, 14:24305990:T:C, 14:24307822:G:GT, 14:24305640:G:A, 14:24307418:T:C, 14:24305758:G:C, 14:24306131:C:T, 14:24305953:A:G, 14:24305730:C:A, 14:24306418:A:G, 14:24306059:AC:A, 14:24307842:G:A, 14:24307837:T:G, 14:24306095:G:T, 14:24306109:C:T, 14:24307822:G:A, 14:24306077:G:A, 14:24307824:A:T, 14:24306080:C:T, 14:24305649:C:T, 14:24306433:G:GA, 14:24306420:G:C, 14:24305658:T:G, 14:24306472:C:T, 14:24307412:TC:T, 14:24306062:C:A, 14:24306044:G:C, 14:24306047:G:T, 14:24306126:CAG:C, 14:24306449:C:G, 14:24307391:G:A, or 14:24307857:A:C (according to GRCh38/hg38 human genome assembly coordinates).

The present disclosure also provides compositions comprising therapeutic agents that treat or inhibit a liver disease for use in the preparation of a medicament for treatment of a liver disease in a subject having one or more CIDEB variant nucleic acid molecules comprising: 14:24305635:A:AGTAG, 14:24305641:A:C, 14:24305650:G:A, 14:24305657:C:A, 14:24305662:G:T, 14:24305667:T:C, 14:24305671:C:A, 14:24305671:C:G, 14:24305701:A:T, 14:24305709:C:T, 14:24305718:A:G, 14:24305721:T:C, 14:24305728:G:GGCCTT, 14:24305743:T:C, 14:24305948:T:C, 14:24305966:C:T, 14:24305974:T:C, 14:24305980:TCA:T, 14:24305988:C:T, 14:24306014:C:T, 14:24306034:A:C, 14:24306041:C:G, 14:24306044:G:A, 14:24306047:G:A, 14:24306051:T:G, 14:24306064:T:C, 14:24306074:A:G, 14:24306077:G:C, 14:24306082:A:G, 14:24306083:T:A, 14:24306095:G:A, 14:24306122:A:G, 14:24306134:C:G, 14:24306373:C:G, 14:24306379:T:C, 14:24306382:G:A, 14:24306383:G:T, 14:24306426:T:G, 14:24306437:C:G, 14:24306439:G:C, 14:24306442:A:G, 14:24306444:A:G, 14:24306457:C:T, 14:24306463:C:T, 14:24306469:C:T, 14:24306480:A:G, 14:24306486:A:C, 14:24306504:A:G, 14:24306519:A:G, 14:24307382:G:C, 14:24307405:A:G, 14:24307417:A:T, 14:24307421:T:A, 14:24307441:C:A, 14:24307444:A:C, 14:24307444:A:G, 14:24307450:C:CGCTG, 14:24307461:TG:T, 14:24307469:AG:A, 14:24307474:C:T, 14:24307475:A:G, 14:24307833:G:C, 14:24307851:T:TAC, 14:24306426:T:C, 14:24307849:G:C, 14:24307448:G:T, 14:24305671:C:T, 14:24305663:C:T, 14:24305686:C:G, 14:24307829:A:C, 14:24307818:CTGAG:C, 14:24307856:C:T, 14:24306423:T:C, 14:24306061:AC:A, 14:24307390:C:T, 14:24306382:G:T, 14:24306373:C:T, 14:24305733:T:C, 14:24307858:T:C, 14:24306387:C:T, 14:24305637:T:C, 14:24306062:C:T, 14:24307853:C:G, 14:24307450:C:G, 14:24306052:TG:T, 14:24305673:G:A, 14:24306043:C:T, 14:24307834:G:A, 14:24306417:C:T, 14:24307451:G:A, 14:24307436:A:C, 14:24305953:ACTTT:A, 14:24306489:G:T, 14:24307441:C:T, 14:24306375:C:T, 14:24305657:C:G, 14:24306427:C:T, 14:24306524:C:T, 14:24307516:C:A, 14:24307840:G:C, 14:24307501:A:G, 14:24305968:A:C, 14:24305986:C:T, 14:24307441:C:G, 14:24307459:G:T, 14:24306017:T:A, 14:24307424:G:A, 14:24306072:G:T, 14:24307423:C:T, 14:24307450:C:T, 14:24306420:G:A, 14:24307454:G:A, 14:24305653:C:T, 14:24307442:G:A, 14:24306002:C:T, 14:24306076:C:T, 14:24305664:C:T, 14:24305961:TG:T, 14:24305706:A:G, 14:24305946:C:T, 14:24306455:G:C, 14:24307468:G:A, 14:24307825:A:C, 14:24306110:G:A, 14:24305710:C:T, 14:24307483:C:T, 14:24306459:A:G, 14:24305754:C:T, 14:24305650:G:C, 14:24305691:C:T, 14:24306508:G:C, 14:24306039:G:T, 14:24306139:T:C, 14:24306391:T:C, 14:24306373:C:A, 14:24307498:C:T, 14:24307415:G:A, 14:24306138:CTG:C, 14:24307453:T:C, 14:24305692:G:A, 14:24305683:C:G, 14:24307484:G:A, 14:24307385:C:T, 14:24306519:A:T, 14:24307839:A:C, 14:24305965:C:T, 14:24305988:CAT:C, 14:24306087:C:G, 14:24307439:C:T, 14:24307477:A:C, 14:24306436:G:T, 14:24306507:A:G, 14:24307397:C:T, 14:24307495:G:A, 14:24306034:A:T, 14:24306013:G:A, 14:24307381:A:G, 14:24306383:G:C, 14:24305638:A:G, 14:24307420:G:A, 14:24306020:C:T, 14:24306470:A:C, 14:24307435:C:T, 14:24306469:C:G, 14:24306451:C:T, 14:24306403:G:A, 14:24307515:C:G, 14:24307489:A:G, 14:24307414:C:T, 14:24306483:A:G, 14:24305755:G:A, 14:24305766:C:T, 14:24306064:T:G, 14:24307516:C:G, 14:24305766:C:G, 14:24306489:G:A, 14:24306097:T:C, 14:24305763:T:G, 14:24307447:G:A, 14:24307402:G:A, 14:24305972:C:G, 14:24306423:T:G, 14:24305974:T:TG, 14:24307411:T:C, 14:24306121:T:C, 14:24307516:C:T, 14:24306424:C:T, 14:24306039:G:C, 14:24307853:C:A, 14:24306388:A:G, 14:24305990:T:C, 14:24307822:G:GT, 14:24305640:G:A, 14:24307418:T:C, 14:24305758:G:C, 14:24306131:C:T, 14:24305953:A:G, 14:24305730:C:A, 14:24306418:A:G, 14:24306059:AC:A, 14:24307842:G:A, 14:24307837:T:G, 14:24306095:G:T, 14:24306109:C:T, 14:24307822:G:A, 14:24306077:G:A, 14:24307824:A:T, 14:24306080:C:T, 14:24305649:C:T, 14:24306433:G:GA, 14:24306420:G:C, 14:24305658:T:G, 14:24306472:C:T, 14:24307412:TC:T, 14:24306062:C:A, 14:24306044:G:C, 14:24306047:G:T, 14:24306126:CAG:C, 14:24306449:C:G, 14:24307391:G:A, or 14:24307857:A:C (according to GRCh38/hg38 human genome assembly coordinates).

The present disclosure also provides compositions comprising one or more CIDEB inhibitors, one or more PNPLA3 inhibitors, or one or more HSD17B13 inhibitors, or any combination thereof, for use in the treatment of a liver disease in a subject having one or more CIDEB variant nucleic acid molecules comprising: 14:24305635:A:AGTAG, 14:24305641:A:C, 14:24305650:G:A, 14:24305657:C:A, 14:24305662:G:T, 14:24305667:T:C, 14:24305671:C:A, 14:24305671:C:G, 14:24305701:A:T, 14:24305709:C:T, 14:24305718:A:G, 14:24305721:T:C, 14:24305728:G:GGCCTT, 14:24305743:T:C, 14:24305948:T:C, 14:24305966:C:T, 14:24305974:T:C, 14:24305980:TCA:T, 14:24305988:C:T, 14:24306014:C:T, 14:24306034:A:C, 14:24306041:C:G, 14:24306044:G:A, 14:24306047:G:A, 14:24306051:T:G, 14:24306064:T:C, 14:24306074:A:G, 14:24306077:G:C, 14:24306082:A:G, 14:24306083:T:A, 14:24306095:G:A, 14:24306122:A:G, 14:24306134:C:G, 14:24306373:C:G, 14:24306379:T:C, 14:24306382:G:A, 14:24306383:G:T, 14:24306426:T:G, 14:24306437:C:G, 14:24306439:G:C, 14:24306442:A:G, 14:24306444:A:G, 14:24306457:C:T, 14:24306463:C:T, 14:24306469:C:T, 14:24306480:A:G, 14:24306486:A:C, 14:24306504:A:G, 14:24306519:A:G, 14:24307382:G:C, 14:24307405:A:G, 14:24307417:A:T, 14:24307421:T:A, 14:24307441:C:A, 14:24307444:A:C, 14:24307444:A:G, 14:24307450:C:CGCTG, 14:24307461:TG:T, 14:24307469:AG:A, 14:24307474:C:T, 14:24307475:A:G, 14:24307833:G:C, 14:24307851:T:TAC, 14:24306426:T:C, 14:24307849:G:C, 14:24307448:G:T, 14:24305671:C:T, 14:24305663:C:T, 14:24305686:C:G, 14:24307829:A:C, 14:24307818:CTGAG:C, 14:24307856:C:T, 14:24306423:T:C, 14:24306061:AC:A, 14:24307390:C:T, 14:24306382:G:T, 14:24306373:C:T, 14:24305733:T:C, 14:24307858:T:C, 14:24306387:C:T, 14:24305637:T:C, 14:24306062:C:T, 14:24307853:C:G, 14:24307450:C:G, 14:24306052:TG:T, 14:24305673:G:A, 14:24306043:C:T, 14:24307834:G:A, 14:24306417:C:T, 14:24307451:G:A, 14:24307436:A:C, 14:24305953:ACTTT:A, 14:24306489:G:T, 14:24307441:C:T, 14:24306375:C:T, 14:24305657:C:G, 14:24306427:C:T, 14:24306524:C:T, 14:24307516:C:A, 14:24307840:G:C, 14:24307501:A:G, 14:24305968:A:C, 14:24305986:C:T, 14:24307441:C:G, 14:24307459:G:T, 14:24306017:T:A, 14:24307424:G:A, 14:24306072:G:T, 14:24307423:C:T, 14:24307450:C:T, 14:24306420:G:A, 14:24307454:G:A, 14:24305653:C:T, 14:24307442:G:A, 14:24306002:C:T, 14:24306076:C:T, 14:24305664:C:T, 14:24305961:TG:T, 14:24305706:A:G, 14:24305946:C:T, 14:24306455:G:C, 14:24307468:G:A, 14:24307825:A:C, 14:24306110:G:A, 14:24305710:C:T, 14:24307483:C:T, 14:24306459:A:G, 14:24305754:C:T, 14:24305650:G:C, 14:24305691:C:T, 14:24306508:G:C, 14:24306039:G:T, 14:24306139:T:C, 14:24306391:T:C, 14:24306373:C:A, 14:24307498:C:T, 14:24307415:G:A, 14:24306138:CTG:C, 14:24307453:T:C, 14:24305692:G:A, 14:24305683:C:G, 14:24307484:G:A, 14:24307385:C:T, 14:24306519:A:T, 14:24307839:A:C, 14:24305965:C:T, 14:24305988:CAT:C, 14:24306087:C:G, 14:24307439:C:T, 14:24307477:A:C, 14:24306436:G:T, 14:24306507:A:G, 14:24307397:C:T, 14:24307495:G:A, 14:24306034:A:T, 14:24306013:G:A, 14:24307381:A:G, 14:24306383:G:C, 14:24305638:A:G, 14:24307420:G:A, 14:24306020:C:T, 14:24306470:A:C, 14:24307435:C:T, 14:24306469:C:G, 14:24306451:C:T, 14:24306403:G:A, 14:24307515:C:G, 14:24307489:A:G, 14:24307414:C:T, 14:24306483:A:G, 14:24305755:G:A, 14:24305766:C:T, 14:24306064:T:G, 14:24307516:C:G, 14:24305766:C:G, 14:24306489:G:A, 14:24306097:T:C, 14:24305763:T:G, 14:24307447:G:A, 14:24307402:G:A, 14:24305972:C:G, 14:24306423:T:G, 14:24305974:T:TG, 14:24307411:T:C, 14:24306121:T:C, 14:24307516:C:T, 14:24306424:C:T, 14:24306039:G:C, 14:24307853:C:A, 14:24306388:A:G, 14:24305990:T:C, 14:24307822:G:GT, 14:24305640:G:A, 14:24307418:T:C, 14:24305758:G:C, 14:24306131:C:T, 14:24305953:A:G, 14:24305730:C:A, 14:24306418:A:G, 14:24306059:AC:A, 14:24307842:G:A, 14:24307837:T:G, 14:24306095:G:T, 14:24306109:C:T, 14:24307822:G:A, 14:24306077:G:A, 14:24307824:A:T, 14:24306080:C:T, 14:24305649:C:T, 14:24306433:G:GA, 14:24306420:G:C, 14:24305658:T:G, 14:24306472:C:T, 14:24307412:TC:T, 14:24306062:C:A, 14:24306044:G:C, 14:24306047:G:T, 14:24306126:CAG:C, 14:24306449:C:G, 14:24307391:G:A, or 14:24307857:A:C (according to GRCh38/hg38 human genome assembly coordinates). The CIDEB inhibitors, PNPLA3 inhibitors, and/or HSD17B13 inhibitors can be any of the CIDEB inhibitors, PNPLA3 inhibitors, and/or HSD17B13 inhibitors described herein.

The present disclosure also provides one or more CIDEB inhibitors, one or more PNPLA3 inhibitors, and/or one or more HSD17B13 inhibitors for use in the preparation of a medicament for treatment of a liver disease in a subject having one or more CIDEB variant nucleic acid molecules comprising: 14:24305635:A:AGTAG, 14:24305641:A:C, 14:24305650:G:A, 14:24305657:C:A, 14:24305662:G:T, 14:24305667:T:C, 14:24305671:C:A, 14:24305671:C:G, 14:24305701:A:T, 14:24305709:C:T, 14:24305718:A:G, 14:24305721:T:C, 14:24305728:G:GGCCTT, 14:24305743:T:C, 14:24305948:T:C, 14:24305966:C:T, 14:24305974:T:C, 14:24305980:TCA:T, 14:24305988:C:T, 14:24306014:C:T, 14:24306034:A:C, 14:24306041:C:G, 14:24306044:G:A, 14:24306047:G:A, 14:24306051:T:G, 14:24306064:T:C, 14:24306074:A:G, 14:24306077:G:C, 14:24306082:A:G, 14:24306083:T:A, 14:24306095:G:A, 14:24306122:A:G, 14:24306134:C:G, 14:24306373:C:G, 14:24306379:T:C, 14:24306382:G:A, 14:24306383:G:T, 14:24306426:T:G, 14:24306437:C:G, 14:24306439:G:C, 14:24306442:A:G, 14:24306444:A:G, 14:24306457:C:T, 14:24306463:C:T, 14:24306469:C:T, 14:24306480:A:G, 14:24306486:A:C, 14:24306504:A:G, 14:24306519:A:G, 14:24307382:G:C, 14:24307405:A:G, 14:24307417:A:T, 14:24307421:T:A, 14:24307441:C:A, 14:24307444:A:C, 14:24307444:A:G, 14:24307450:C:CGCTG, 14:24307461:TG:T, 14:24307469:AG:A, 14:24307474:C:T, 14:24307475:A:G, 14:24307833:G:C, 14:24307851:T:TAC, 14:24306426:T:C, 14:24307849:G:C, 14:24307448:G:T, 14:24305671:C:T, 14:24305663:C:T, 14:24305686:C:G, 14:24307829:A:C, 14:24307818:CTGAG:C, 14:24307856:C:T, 14:24306423:T:C, 14:24306061:AC:A, 14:24307390:C:T, 14:24306382:G:T, 14:24306373:C:T, 14:24305733:T:C, 14:24307858:T:C, 14:24306387:C:T, 14:24305637:T:C, 14:24306062:C:T, 14:24307853:C:G, 14:24307450:C:G, 14:24306052:TG:T, 14:24305673:G:A, 14:24306043:C:T, 14:24307834:G:A, 14:24306417:C:T, 14:24307451:G:A, 14:24307436:A:C, 14:24305953:ACTTT:A, 14:24306489:G:T, 14:24307441:C:T, 14:24306375:C:T, 14:24305657:C:G, 14:24306427:C:T, 14:24306524:C:T, 14:24307516:C:A, 14:24307840:G:C, 14:24307501:A:G, 14:24305968:A:C, 14:24305986:C:T, 14:24307441:C:G, 14:24307459:G:T, 14:24306017:T:A, 14:24307424:G:A, 14:24306072:G:T, 14:24307423:C:T, 14:24307450:C:T, 14:24306420:G:A, 14:24307454:G:A, 14:24305653:C:T, 14:24307442:G:A, 14:24306002:C:T, 14:24306076:C:T, 14:24305664:C:T, 14:24305961:TG:T, 14:24305706:A:G, 14:24305946:C:T, 14:24306455:G:C, 14:24307468:G:A, 14:24307825:A:C, 14:24306110:G:A, 14:24305710:C:T, 14:24307483:C:T, 14:24306459:A:G, 14:24305754:C:T, 14:24305650:G:C, 14:24305691:C:T, 14:24306508:G:C, 14:24306039:G:T, 14:24306139:T:C, 14:24306391:T:C, 14:24306373:C:A, 14:24307498:C:T, 14:24307415:G:A, 14:24306138:CTG:C, 14:24307453:T:C, 14:24305692:G:A, 14:24305683:C:G, 14:24307484:G:A, 14:24307385:C:T, 14:24306519:A:T, 14:24307839:A:C, 14:24305965:C:T, 14:24305988:CAT:C, 14:24306087:C:G, 14:24307439:C:T, 14:24307477:A:C, 14:24306436:G:T, 14:24306507:A:G, 14:24307397:C:T, 14:24307495:G:A, 14:24306034:A:T, 14:24306013:G:A, 14:24307381:A:G, 14:24306383:G:C, 14:24305638:A:G, 14:24307420:G:A, 14:24306020:C:T, 14:24306470:A:C, 14:24307435:C:T, 14:24306469:C:G, 14:24306451:C:T, 14:24306403:G:A, 14:24307515:C:G, 14:24307489:A:G, 14:24307414:C:T, 14:24306483:A:G, 14:24305755:G:A, 14:24305766:C:T, 14:24306064:T:G, 14:24307516:C:G, 14:24305766:C:G, 14:24306489:G:A, 14:24306097:T:C, 14:24305763:T:G, 14:24307447:G:A, 14:24307402:G:A, 14:24305972:C:G, 14:24306423:T:G, 14:24305974:T:TG, 14:24307411:T:C, 14:24306121:T:C, 14:24307516:C:T, 14:24306424:C:T, 14:24306039:G:C, 14:24307853:C:A, 14:24306388:A:G, 14:24305990:T:C, 14:24307822:G:GT, 14:24305640:G:A, 14:24307418:T:C, 14:24305758:G:C, 14:24306131:C:T, 14:24305953:A:G, 14:24305730:C:A, 14:24306418:A:G, 14:24306059:AC:A, 14:24307842:G:A, 14:24307837:T:G, 14:24306095:G:T, 14:24306109:C:T, 14:24307822:G:A, 14:24306077:G:A, 14:24307824:A:T, 14:24306080:C:T, 14:24305649:C:T, 14:24306433:G:GA, 14:24306420:G:C, 14:24305658:T:G, 14:24306472:C:T, 14:24307412:TC:T, 14:24306062:C:A, 14:24306044:G:C, 14:24306047:G:T, 14:24306126:CAG:C, 14:24306449:C:G, 14:24307391:G:A, or 14:24307857:A:C (according to GRCh38/hg38 human genome assembly coordinates). The CIDEB inhibitors, PNPLA3 inhibitors, and/or HSD17B13 inhibitors can be any of the CIDEB inhibitors, PNPLA3 inhibitors, and/or HSD17B13 inhibitors described herein.

The present disclosure also provides methods of treating a subject having a liver disease or at risk of developing a liver disease, wherein: when the subject is homozygous for a nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide, the subject is administered a CIDEB inhibitor in an amount that is the same as or greater than a standard dosage amount, or is administered a combination of a CIDEB inhibitor in an amount that is the same as or greater than a standard dosage amount and an HSD17B13 inhibitor and/or a PNPLA3 inhibitor; and when the subject is not homozygous for a nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide (i.e., is a carrier for a loss-of-function HSD17B13), the subject is administered a CIDEB inhibitor in an amount that is less than a standard dosage amount. The CIDEB inhibitors, PNPLA3 inhibitors, and/or HSD17B13 inhibitors can be any of the CIDEB inhibitors and/or HSD17B13 inhibitors described herein.

The present disclosure also provides methods of treating a subject with a CIDEB inhibitor, wherein the subject has a liver disease or is at risk of developing a liver disease, the methods comprising: determining whether the subject has a nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide by: obtaining or having obtained a biological sample from the subject; and performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising the nucleic acid molecule encoding the reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide; and when the subject is homozygous for a nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide, the subject is administered a CIDEB inhibitor in an amount that is the same as or greater than a standard dosage amount, or is administered a combination of a CIDEB inhibitor and an HSD17B13 inhibitor and/or a PNPLA3 inhibitor; and when the subject is not homozygous for a nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide (i.e., is a carrier for a loss-of-function HSD17B13), the subject is administered a CIDEB inhibitor in an amount that is less than a standard dosage amount; wherein the presence of a genotype having the nucleic acid molecule encoding the reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide indicates the subject is a candidate for treatment with the CIDEB inhibitor.

All patent documents, websites, other publications, accession numbers and the like cited above or below are incorporated by reference in their entirety for all purposes to the same extent as if each individual item were specifically and individually indicated to be so incorporated by reference. If different versions of a sequence are associated with an accession number at different times, the version associated with the accession number at the effective filing date of this application is meant. The effective filing date means the earlier of the actual filing date or filing date of a priority application referring to the accession number if applicable. Likewise, if different versions of a publication, website or the like are published at different times, the version most recently published at the effective filing date of the application is meant unless otherwise indicated. Any feature, step, element, embodiment, or aspect of the present disclosure can be used in combination with any other feature, step, element, embodiment, or aspect unless specifically indicated otherwise. Although the present disclosure has been described in some detail by way of illustration and example for purposes of clarity and understanding, it will be apparent that certain changes and modifications may be practiced within the scope of the appended claims.

The following examples are provided to describe the embodiments in greater detail. They are intended to illustrate, not to limit, the claimed embodiments. The following examples provide those of ordinary skill in the art with a disclosure and description of how the compounds, compositions, articles, devices and/or methods described herein are made and evaluated, and are intended to be purely exemplary and are not intended to limit the scope of any claims. Efforts have been made to ensure accuracy with respect to numbers (such as, for example, amounts, temperature, etc.), but some errors and deviations may be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in ° C. or is at ambient temperature, and pressure is at or near atmospheric.

EXAMPLES Example 1: General Methodology and Frequency of Rare Coding Variants in CIDEB Across Populations

Study Participants

Discovery exome-wide association analyses were performed in the UK Biobank (UKB) cohort and in the MyCode Community Health Initiative from Geisinger Health System (GHS). The UKB is a population-based cohort including individuals 40-69 years of age recruited at 22 testing sites in the UK between 2006-2010. 411,926 European ancestry, 9,830 South Asian ancestry, 8,544 African ancestry, 2,108 East Asian ancestry, and 587 American ancestry participants with available whole-exome sequencing and transaminase data were included. MyCode is a health system-based cohort of patients from rural Pennsylvania (USA) recruited in 2007-2021. 109,909 European ancestry participants with available whole-exome sequencing and transaminase data were included. Liver disease outcome association analyses further included up to 28,948 participants from the Malmö Diet and Cancer Study (MDCS). 13,418 participants from the University of Pennsylvania PennMedicine BioBank (UPENN-PMBB) and 23,849 participants from the Mount Sinai BioMe BioBank cohort (BioMe). Liver-histopathology association analyses were also performed in 3,599 bariatric surgery patients from GHS who were not included in the primary discovery analyses.

DNA Exome Sequencing

NimbleGen VCRome probes (for part of GHS) or a modified version of the xGen design available from Integrated DNA Technologies (IDT; for the rest of GHS and for other cohorts) were used to capture exome sequences. Following capture, balanced pools were sequenced using 75 bp paired-end reads on Illumina v4 HiSeq 2500 (for part of the GHS cohort) or NovaSeq (for the rest of GHS and for other cohorts) instruments. Sequencing achieved greater than 20× coverage over 85% of targeted bases in 96% of VCRome samples and 20× coverage over 90% of targeted bases in 99% of IDT samples. Following sequencing, pooled samples were demultiplexed using Illumina software, aligned sequenced reads to the GRCh38 Human Genome reference sequence using BWA-mem, and generated cohort-level genotype files with GLnexus.

Variants were annotated using the snpEff software and Ensembl v85 gene definitions. Annotations were prioritized for protein-coding transcripts based on the most deleterious functional effect for each gene based with the following hierarchy (from most to least deleterious): frameshift, stop-gain, stop-loss, splice acceptor, splice donor, in-frame indel, missense, other annotations. Predicted LOF genetic variants included: a) insertions or deletions resulting in a frameshift, b) insertions, deletions or single nucleotide variants resulting in the introduction of a premature stop codon or in the loss of the transcription start site or stop site, and c) variants in donor or acceptor splice sites. Missense variants were classified for likely functional impact according to the number of in silico prediction algorithms that predicted deleteriousness using SIFT, Polyphen2_HDIV and Polyphen2_HVAR, LRT and MutationTaster. For each gene, the alternative allele frequency (AAF) and functional annotation of each variant determined inclusion into these 7 gene burden exposures: 1) pLOF variants with AAF<1%; 2) pLOF or missense variants predicted deleterious by 5/5 algorithms with AAF<1%; 3) pLOF or missense variants predicted deleterious by 5/5 algorithms with AAF<0.1%; 4) pLOF or missense variants predicted deleterious by at least 1/5 algorithms with AAF<1%; 5) pLOF or missense variants predicted deleterious by at least 1/5 algorithms with AAF<0.1%; 6) pLOF or any missense with AAF<1%; 7) pLOF or any missense variants with AAF<0.1%.

Phenotype Definitions

For continuous traits, data cleaning was performed by removing non-physiologic lab values, or results stemming from invalid or contaminated specimens. In Geisinger Health System (GHS), the median transaminase values for each individual were extracted from electronic health records. In the UK Biobank (UKB), transaminases were measured using a Beckman Coulter AU5800 at the baseline study visit.

Cases of binary liver disease outcomes were defined based on one or more of the following criteria: i) self-reported disease obtained from digital questionnaire or interview with a trained nurse, ii) in-patient hospitalization for the disease or clinical-problem list entries of the disease according to International Classification of Diseases, Ninth (ICD-9) or Tenth (ICD-10) Revision diagnosis code, iii) medical procedures or surgery due to the disease, iv) death due to the disease, and v) a disease diagnosis code entered for two or more outpatient visits in separate calendar days. The specific entries used to define different types of liver disease are described in detail in Table 17. Controls were defined as individuals who did not meet any of the criteria for case status. To minimize misclassification, the following were excluded from the control group: i) non-cases diagnosed with any type of liver disease (not restricted to the type of liver disease in question), ii) non-cases with only one out-patient encounter related to the type of liver disease in question, iii) non-cases diagnosed with ascites presumably related to liver failure, and iv) non-cases with elevated alanine aminotransferase (ALT) levels (>33 IU/L for men, >25 IU/L for women).

TABLE 17 Definition of liver disease outcomes based on health surveys and electronic health records Liver disease outcome Case definition Liver disease (any) ICD10: K70(Alcoholic liver disease), K71(Toxic liver disease), K72(Hepatic failure, not elsewhere classified), K73(Chronic hepatitis, not elsewhere classified), K74(Fibrosis and cirrhosis of liver), K75(Other inflammatory liver diseases), K76(Other diseases of liver), K77(Liver disorders in diseases classified elsewhere), I81(Portal vein thrombosis), I85(Secondary esophageal varices without bleeding), I982(Esophageal varices without bleeding in diseases classified elsewhere), I983(Esophageal varices with bleeding in diseases classified elsewhere), I864(Gastric varices), T864(Complications of liver transplant), Z944(Liver transplant status), C220(Liver cell carcinoma). Procedure codes according to OPCS4 classification: G10(Open operations on varices of esophagus), G144(Fiberoptic endoscopic injection sclerotherapy to varices of esophagus), J01(Transplantation of liver). Procedure codes according to NOMESCO classification version 1: JJC(liver transplant), JCA20(ligature of esophageal varices), JCA22(endoscopic ligature of esophageal varices), JDA22(endoscopic ligature of varices of stomach), TJC00(insertion of balloon tube for tamponade of esophageal varices [sengstaken- blakemore]). Procedure codes according to NOMESCO classification version 6: 5200(liver transplant), 5201(exploration of transplanted liver), 5212(resection of transplanted liver), 5214(extracorporeal resection of liver prior to transplant), 5219(other types of resection of transplanted liver), 5280(biopsy from transplanted liver), 5282(percutaneous liver biopsy from transplanted liver). Self-report: alcoholic liver disease, alcoholic cirrhosis, liver failure cirrhosis, esophageal varices. Alcoholic liver disease ICD10: K70(Alcoholic liver disease) Non-alcoholic liver disease ICD10: K721(Chronic hepatic failure), K740(Hepatic fibrosis), K741(Hepatic sclerosis), K742(Hepatic fibrosis with hepatic sclerosis), K746(Other and unspecified cirrhosis of liver), K758(Other specified inflammatory liver diseases), K760(Fatty [change of] liver, not elsewhere classified) Liver cirrhosis (any) ICD10: K703(Cirrhosis), K704(Alcoholic hepatic failure), K717(Toxic liver disease with fibrosis and cirrhosis of liver), K721(Chronic hepatic failure), K746(Other and unspecified cirrhosis of liver) Alcoholic liver cirrhosis ICD10: K703(Cirrhosis), K704(Alcoholic hepatic failure) Non-alcoholic liver cirrhosis ICD10: K746(Other and unspecified cirrhosis of liver) Viral hepatitis ICD10: B15(Acute hepatitis A), B16(Acute hepatitis B), B17(Other acute viral hepatitis), B18(Chronic viral hepatitis), B19(Unspecified viral hepatitis) ICD10 indicates the 10th revision of the International Statistical Classification of Diseases and Related Health Problems; OPCS4 indicates Office of Population Censuses and Surveys (OPCS) Classification of Interventions and Procedures version 4; NOMESCO indicates Nordic Medico-Statistical Committee procedure codes. Participants were excluded from the control population if they were: i) diagnosed with the “any liver disease” outcome codes (as defined in the table), ii) ascites presumably related to liver failure (ICD10 R18 (Ascites), excluding individuals with other potential causes of ascites; C16 (Malignant neoplasm of stomach), C17 (Malignant neoplasm of small intestine), C18 (Malignant neoplasm of colon), C20 (Malignant neoplasm of rectum), 142 (Cardiomyopathy),I50 (Heart failure)) or iii) if they had elevated ALT>33 U/L for men and >25 U/L for women. Liver Histopathologic Phenotype Definitions in the GHS Bariatric Surgery Cohort

The GHS bariatric cohort consists of 3,599 individuals of European descent who underwent bariatric surgery and were enrolled in GHS's MyCode and GHS-Regeneron Genetics Center (RGC) DiscovEHR collaboration. Surgeons took wedge biopsies of the liver 10 cm to the left of falciform ligament prior to any liver retraction or surgery on the stomach, following a standardized protocol. The biopsy was divided into sections, with the primary section delivered to the clinical pathologists for liver histology (fixed in 10% neutral buffered formalin and stained with hematoxylin and eosin for routine histology and Masson's trichrome for assessment of fibrosis) and remaining sections stored within a research biobank (stabilized with the RNAlater tissue collection system (ThermoFisher Scientific) or frozen in liquid nitrogen). An experienced pathologist conducted histological examinations, which were subsequently re-reviewed by a second pathologist, and scored based on the NASH Clinical Research Network system: steatosis Grade 0 (<5% parenchymal involvement), Grade 1 (5 to <34%), Grade 2 (34 to <67%), and Grade 3 (>67%); lobular inflammation Grade 0 (no foci), Grade 1 (mild, <2 foci per 200× field), Grade 2 (moderate, 2-4 foci per 200× field), Grade 3 (severe, >4 foci per 200× field); ballooning Grade 0 (none), Grade 1 (few balloon cells), Grade 2 (many cells/prominent ballooning); fibrosis Stage 0 (none), Stage 1 (perisinusoidal or periportal fibrosis), Stage 2 (perisinusoidal and periportal fibrosis), Stage 3 (bridging fibrosis), and Stage 4 (liver cirrhosis). These histologic diagnoses were used to define the following phenotypes: 1) Normal liver: no evidence of steatosis, nonalcoholic steatohepatitis (NASH), or fibrosis; 2) Simple steatosis: Steatosis (regardless of grade) with no evidence of NASH or fibrosis; 3) NASH: Any presence of lobular inflammation or hepatocyte ballooning (regardless of grade), or any presence of fibrosis (regardless of stage); 4) Fibrosis: Any presence of fibrosis (regardless of stage); 5) Nonalcoholic fatty liver disease (NAFLD) activity score (NAS) defined as the unweighted sum of the scores for steatosis (0-3), lobular inflammation (0-3) and ballooning (0-2), thus ranging from 0-8.

Statistical Analysis

Associations between genotypes and phenotypes were estimated by fitting linear (for quantitative traits) or Firth bias-corrected logistic (for binary traits) regression models using REGENIE v2+(10.1038/s41588-021-00870-7) or the logistf function in R. Analyses were stratified by cohort and ancestry and adjusted for age, age², sex, age-by-sex and age²-by-sex interaction terms, experimental batch-related covariates, the first 10 common variant-derived genetic principal components (PCs), the first 20 rare variant-derived PCs, and a polygenic score generated by REGENIE that accounts for relatedness, population structure, and polygenicity (10.1038/ng.257). To ensure independence between rare and common variants signals, discovery exome-wide analyses for common variant signals identified by fine-mapping were additionally adjusted as previously described. Results across studies were combined by fixed-effect inverse variance-weighted meta-analysis.

Frequency of CIDEB Coding Variants Identified by Exome Sequencing Across Ancestries

Using exome sequencing across ancestry groups as described above, the frequency of homozygous reference genotype (reference-reference, RR), heterozygous alternative allele carrier genotype (reference-alternative, RA) and homozygous alternative allele carrier genotype (alternative-alternative, AA) were determined in sequenced individuals across ancestry groups. In each ancestry group, the RR genotype, which in the genetic analyses were associated with higher liver fat, injury and liver disease risk was the most common genotype (Table 18).

TABLE 18 Genotype frequencies for CIDEB predicted loss-of-function or missense variants identified by exome sequencing across ancestries Ancestry RR genotype, % RA genotype, % AA genotype, % African 98.6% 1.4% 0.001%  American 98.7% 1.3% 0.01% European 99.3% 0.7% 0.001%  East Asian 98.8% 1.2%   0% South Asian 97.8% 2.2% 0.02% Abbreviations: RR, reference-reference genotype; RA, reference-alternative genotype; AA, alternative-alternative genotype for predicted loss-of-function or missense variants in CIDEB. The sum of percentages may differ from 100% due to rounding. GTEx RNA-seq

TMM normalized gene expression matrices per tissue were obtained using GTEx v8 raw expression matrices download from the GTEx portal. Within each tissue, we subset to samples included in the GTEx v8 analysis freeze and filter to genes using the same quality control filters described below.

Liver RNA-Seq in Bariatric Cohort Samples

Liver RNA-seq was performed in 2,304 patients from GHS who underwent a perioperative wedge biopsy of the liver as part of bariatric surgery.

RNA concentration was determined by UV absorbance and 500 ng of total RNA was used for processing. Samples were processed with the NEBNext Poly(A) mRNA Magnetic Isolation Module and NEB NEBNext Ultra II Directional RNA Library Prep Kit for Illumina (New England Biolabs), according to the manufacturer recommendations. Samples were amplified with 10 cycles of PCR with Kapa HiFi polymerase (Roche) and custom barcoded primers (IDT). Samples were sequenced on the Illumina NovaSeq 6000 platform on S2 flow cells with paired-end 75 bp reads. The mean number of reads per sample was 72 million and the median was 68 million; 93% of the samples had at least 50 million reads and 99% of the samples had more than 45 million reads, reflecting high coverage sequencing. The gene expression values for all samples were then normalized across samples using the trimmed mean of m-values approach (TMM) as implemented in edgeR.

RNA-seq data were processed broadly following the GTEx v8 analysis protocol (world wide web at gtexportal.ordhonne/documentationPage #staticTextAnalysisMethods). Briefly, sequenced samples were aligned to the human reference genome GRCh38/hg38 with STAR v2.5.3a. Duplicate marking was applied to optical duplicates only with Picard using the pixel distance setting OPTICAL_DUPLICATE_PIXEL_DISTANCE=15000.

The quantification of mRNA was based on the GENCODE Release 32 annotation (world wide web at gencodegenes.org/human/release_32.html), collapsed to a single transcript model for each gene. Gene-level expression quantification was performed using RNA-SeQC. Gene-level read counts and TPM values were produced using the following read-level filters: 1) reads were uniquely mapped; 2) reads were aligned in proper pairs; 3) the read alignment distance was 6; 4) reads were fully contained within exon boundaries.

Gene expression values for all samples were normalized: 1) read counts were normalized between samples using TMM; 2) genes were selected based on expression thresholds of ≥0.1 TPM in ≥20% of samples and reads (unnormalized) in ≥20% of samples.

Allele Specific Read Counts and Analyses

Read counts per allele generated by counting the number of reads overlapping the variant's position and carrying the allele of interest (reference or alternative). P-values for the observed degree of imbalance in read counts per allele were based on an exact binomial test as implemented in binom.test function in R version 4.0.5 assuming a 50% probability of success under the null.

CIDEB Knockdown in HepG2 Cells

HepG2 (ATCC) cells were cultured in MEM with Earle's salt supplemented with 10% FBS, 1% Penicillin-Streptomycin, and 1% L-glutamine. For siRNA knockdown, cells were transfected with CIDEB siRNA (Smartpool, Dharmacon L-004410-00-0050) or control siRNA (Non-targeting pool, Dharmacon D-001810-10-50) for 48 hours. For OA treatment, cells were treated with 400 μM OA for 24 hours, beginning 24 hours after transfection.

For localization of CIDEB with lipid droplets, cells were fixed in 3% PFA for 20 minutes then permeabilized in 0.1% saponin, blocked in 1% BSA and incubated overnight with primary antibody against CIDEB (1:1000, Abnova H00027141-M01). Alexa Fluor 594 goat anti-mouse IgG (Thermo) was used during the secondary antibody incubation. BODIPY493/503 was incubated for 1 hour during the secondary antibody incubation step followed by a 10-minute incubation with DAPI to stain nuclei. After washing, PBS was replaced with mounting medium for fluorescence microscopy (Ibidi 50001) then imaged using a Zeiss LSM 880 confocal microscope.

For western blotting, cells were lysed in RIPA lysis buffer plus protease and phosphatase inhibitors. Lysate was cleared, quantified, electrophoresed, and transferred to PVDF membranes. Membranes were blocked in Superblock T20 TBS buffer (Thermo 37536) then incubated in primary antibodies (CIDEB: Abnova H00027141-M01 1:1000; GAPDH: HRP-conjugated Sigma G9295). For CIDEB, bound antibody was detected via incubation with anti-mouse IgG, HRP secondary antibody (Cell Signaling 7076, 1:10000 dilution. Supersignal West Pico Plus Chemiluminescent Substrate (Thermo 4579) and Supersignal West Femto Maximum Sensitivity Substrate (Thermo 34094) were used for the development of chemiluminescent signal. Relative protein expression was determined by quantification of CIDEB and GAPDH bands on ImageJ. Data was normalized using GAPDH and control cells.

RNA isolation was performed using the RNeasy mini kit (QIAGEN 74104) with DNase I digestion (QIAGEN 79254) as per manufacturer's instructions. Total of 1 μg of RNA was used for cDNA synthesis using the SuperScript IV VILO cDNA synthesis kit (Thermo 11754050). Gene expression levels were determined using Taqman gene expression assays (Applied Biosystems assay IDs: CIDEB (Hs00205339_m1), GAPDH (Hs02786624_g1)) using the Taqman Fast Advanced Master Mix (Thermo 4444963) with the QuantStudio 6 instrument. The data was normalized using GAPDH and the control cells.

For lipid droplet visualization, cells were incubated with AdipoRed (Lonza PT-7009) for 10 minutes then fixed for 10 minutes in 4% paraformaldehyde (PFA). Cells were washed then incubated with 4′,6-diamidino-2-phenylindole (DAPI) for 10 minutes to stain nuclei. After washing, PBS was replaced with mounting medium for fluorescence microscopy (Ibidi 50001) then imaged using a Zeiss LSM 880 confocal microscope.

For quantification of lipid droplets, lipid droplets were detected in the red channel (excitation at 485 nm and emission at 572 nm) using Laplacian-of-Gaussian blob detection, as implemented in the Scikit-Image Python package. To tune the detection threshold parameter of the blob detection algorithm, lipid droplets were manually marked for six random small regions (250×250 pixels) from three images per experimental group. The number of cells in each field was estimated from the DAPI channel. For each experimental group, the following quantitative endpoints were derived: average lipid droplet size (quantified as lipid droplet volumes), average number of lipid droplets per nucleus, and average cell lipid droplet staining (quantified as total lipid droplet areas per nucleus).

Levels of intracellular triglyceride content was measured using the Triglyceride Assay Kit (Abcam ab65336) according to manufacturer's instructions. Triglyceride content was normalized to total protein content as determined by the DC Protein assay (BioRad 5000111). IL8 protein concentrations in cell media were measured using a Meso Scale Diagnostics Proinflammatory Panel and were normalized to total protein content.

Two-way analysis of variation (ANOVA) was used to determine if an interaction between the effects of oleic acid and CIDEB siRNA was present, with Tukey's multiple comparisons tests with Sidak correction used to determine the pairwise effects of 1) 0 μM vs 400 μM oleic acid in the presence of control siRNA; 2) 0 μM vs 400 μM oleic acid in the presence of CIDEB siRNA; 3) control vs CIDEB siRNA in the presence of 0 μM oleic acid; 4) control vs CIDEB siRNA in the presence of 400 μM oleic acid. Welch's t-test was used to compare effects of control siRNA vs CIDEB siRNA on CIDEB expression via western blot and Taqman analysis since no oleic acid treatment was present. Statistical testing was performed using Prism 9.

Example 2: Loss-of-Function in CIDEB is Associated with Lower Liver Transaminases and Protection Against Liver Disease

To identify genetic factors contributing to predisposition for or protection against chronic liver disease, an exome-sequencing analysis of alanine aminotransferase (ALT), a widely used biomarker of liver damage, was performed in over 500,000 people from the UK Biobank (UKB) cohort and the MyCode Community Health Initiative from Geisinger Health System (GHS). The UKB is a population-based cohort including individuals 40-69 years of age recruited at 22 testing sites in the UK between 2006-2010 (PLoS Med 2015; 12:e1001779). 411,926 European ancestry, 9,830 South Asian ancestry, 8,544 African ancestry, 2,108 East Asian ancestry and 587 American ancestry participants with available whole-exome sequencing and transaminase data were included (Table 19). MyCode is a health system-based cohort of patients from rural Pennsylvania (USA) recruited in 2007-2021 (Genet Med 2016; 18:906-13). 109,909 European ancestry participants with available whole-exome sequencing and transaminase data were included (Table 19).

TABLE 19 Baseline characteristics of individuals included in exome-wide association analyses UKB study GHS study Variable (N = 432,995) (N = 109,909) Age, mean (SD) in years 57 (8) 59 (17) Women, N (%) 234,632 (54) 66,739 (61) Participant ancestry (%) European 411,926 (95.1) 109,909 (100) African 8,544 (2) East Asian 2,108 (0.5) South Asian 9,830 (2.3) Admixed American 587 (0.1) Body mass index, mean (SD) in kg/m² 27.4 (4.8) 31.3 (7.3) Alanine Aminotransferase mean (SD) U/L 23.5 (14.1) 24.8 (11.6) Aspartate Aminotransferase mean (SD) U/L 26.2 (10.2) 23.7 (6.4) Body weight, mean (SD) in kg 78 (16) 89 (24) Body mass index WHO categories, N (%) Underweight 2,111 (0.5) 813 (0.7) (<18.5 kg/m²) Healthy weight 140,560 (32.5) 20,097 (18.3) (18.5 to <25 kg/m²) Overweight 183,668 (42.4) 31,725 (28.9) (25 to <30 kg/m²) Obesity, non-severe 96,834 (22.4) 41,918 (38.1) (30 to <40 kg/m²) Severe obesity 8,105 (1.9) 13,377 (12.2) (40 kg/m²) Blood pressure, mean (SD) in mmHg Systolic 137 (16) 125 (10) Diastolic 82 (8) 74 (6) Low-density lipoprotein cholesterol, 137 (34) 106 (29) mean (SD) in mg/dL Triglycerides, median (IQR) in mg/dL 131 (98) 125 (82) Abbreviations: UKB, UK Biobank; GHS, Geisinger Health System; SD, standard deviation; N, number of participants; WHO, World Health Organization; kg/m², kilograms per square meter; mg/dL, milligrams per deciliter; mmHg, millimeters of mercury; IQR, inter-quartile range.

For each gene in the genome, associations with ALT were estimated for the burden of rare predicted loss-of-function (pLOF) and missense variants identified by exome sequencing (see Methods in Example 1). Statistically significant findings for a novel association in the CIDEB gene were subsequently evaluated for their association with: 1) aspartate aminotransferase (AST), another transaminase often associated with liver damage, 2) liver disease clinical outcomes, and 3) liver histopathology (see Methods in Example 1).

In the exome-wide analysis, the burden of rare (alternative allele frequency (AAF)<1%) predicted loss-of-function (pLOF) or missense genetic variants in the CIDEB gene was strongly associated with lower ALT at the exome-wide level of statistical significance (p<3.6×10⁻⁷, a Bonferroni correction for 20,000 genes and seven variant selection models, Table 20), a novel association. Rare pLOF or missense variants in CIDEB were also associated with lower AST levels (Table 20).

TABLE 20 Associations with lower transaminase levels for the burden of rare pLOF plus missense variants in the CIDEB gene (gene = CIDEB; genetic exposure = pLOF plus any missense, AAF <1%) Beta (95% CI), AAF, Genotype counts, Outcome per allele p fraction of 1 RR|RA|AA genotypes ALT −0.09 (−0.12, −0.06) SD, 4.8 × 10⁻⁰⁹ 0.00333 539,292|3,609|3 −1.24 (−1.66, −0.83) U/L AST −0.10 (−0.13, −0.07) SD, 1.0 × 10⁻⁰⁹ 0.00333 536,658|3,589|3 −0.95 (−1.26, −0.65) U/L Abbreviations: CI, confidence interval; SD, standard deviation; U/L, unit liter; AAF, alternative allele frequency; RR, reference-reference genotype; RA, reference-alternative heterozygous genotype; AA, alternative-alternative homozygous genotype; pLOF, predicted loss of function.

An association for rare CIDEB pLOF variants alone (excluding missense variants) with lower transaminases was also observed (Table 21), indicating that the association for rare pLOF plus missense variants reflects a loss-of-function in CIDEB.

TABLE 21 Associations with lower transaminase levels for the burden of rare pLOF variants in the CIDEB gene (gene = CIDEB; genetic exposure = pLOF, AAF <1%) Beta (95% CI), AAF, Genotype counts, Outcome per allele p fraction of 1 RR|RA|AA genotypes ALT −0.12 (−0.18, −0.05) SD, 6.6 × 10⁻⁰⁴ 0.0007 542,144|760|0 −1.57 (−2.48, −0.67) U/L AST −0.12 (−0.19, −0.06) SD, 2.8 × 10⁻⁰⁴ 0.0007 539,495|755|0 −1.25 (−1.91, −0.58) U/L Abbreviations: CI, confidence interval; SD, standard deviation; U/L, unit liter; AAF, alternative allele frequency; RR, reference-reference genotype; RA, reference-alternative heterozygous genotype; AA, alternative-alternative homozygous genotype; pLOF, predicted loss of function.

The associations of CIDEB rare coding variants with risk of liver disease outcomes across etiologies and severity spectrum we estimated. Rare coding variants in CIDEB were associated with: 1) lower risk of any-cause, alcoholic and nonalcoholic liver disease, 2) lower risk of any-cause, alcoholic and nonalcoholic cirrhosis, and 3) lower risk of viral hepatitis. Heterozygous carriers of rare coding variants had 29-53% lower odds of these outcomes compared with non-carriers (FIG. 1 ). On the log-linear scale and in the same set of individuals, the protective associations for rare coding variants in CIDEB were 3- to 7-fold larger than the rs72613567 splice LOF variant in the HSD17B13 gene previously reported to be associated with protection against liver disease (N. Engl. J. Med., 2018, 378, 1096-106) (FIG. 1 ).

Associations with liver histopathology phenotypes in 3,599 bariatric surgery patients who underwent a perioperative liver biopsy (see Methods in Example 1) were estimated. Individuals carrying rare pLOF or missense variants in CIDEB had lower odds of biopsy-defined hepatic steatosis, NASH or fibrosis compared to non-carriers (per-allele odds ratio (OR), 0.34; 95% confidence interval, 0.14 to 0.79; p=0.012; FIG. 2 , panel a). This association was driven by both a lower proportion of bariatric patients with simple steatosis and a lower proportion of patients with NASH or fibrosis among carriers (Table 22). Rare pLOF or missense variants in CIDEB were also associated with a lower NASH-CRN nonalcoholic fatty-liver disease activity score (NAS) at biopsy (per-allele beta in standard deviation units of the score, −0.56, 95% CI −0.88 to −0.24; per-allele beta in untransformed score units, −0.98; 95% CI −1.54 to −0.41; p=7×10⁻⁴, FIG. 2 , panel b and Table 22).

TABLE 22 Association between rare pLOF or rare missense variants in CIDEB and liver histopathology phenotypes OR or CIDEB genotype beta_(SD) counts Outcome (95% CI) P-value (Ref/Het/Hom) Steatosis/NASH/ 0.34 0.012 Cases: 2778/15/0; fibrosis vs. (0.14 to 0.79) Controls: 795/11/0 normal liver Simple steatosis vs. 0.37 0.05 Cases: 1206/7/0; normal liver (0.14 to 1.00) Controls: 795/11/0 NASH/fibrosis vs. 0.25 0.007 Cases: 1572/8/0; normal liver (0.09 to 0.69) Controls: 795/11/0 NAFLD −0.56 0.0007 Participants: activity score (−0.88 to −0.24) 3540/25/0 Abbreviations: OR, odds ratio; SD, standard deviation; CI, confidence interval; Ref, homozygous reference genotype; Het, heterozygous carrier of rare pLOF or missense variant in CIDEB; Hom, homozygous carrier of rare pLOF or missense variant in CIDEB; NASH; nonalcoholic steatohepatitis; NAFLD, nonalcoholic fatty liver disease.

Associations with lipid, glycemic, and anthropometric traits for rare coding variants in CIDEB in over 500,000 people (FIG. 3 ) were estimated. Statistically significant associations for CIDEB pLOF or missense variants were not found with these traits, except for a nominally significant association with lower risk of type 2 diabetes (per-allele odds ratio, 0.87; 95% CI, 0.79 to 0.97; p=0.011).

Furthermore, whether rare pLOF or missense variants in CIDEB were associated with any of 6,040 clinical phenotypes was explored in a phenome-wide wide analysis in the GHS, UKB, or a meta-analysis of these two cohorts. In this analysis, no statistically significant associations were observed with clinical phenotypes other than the associations with lower liver enzymes and outcomes described above, after correction for the number of statistical tests performed (p<8.3×10⁻⁶).

The associations between CIDEB and liver phenotypes were driven by multiple rare pLOF or missense variants in the CIDEB gene (Table 23).

TABLE 23 Missense or pLOF variants of CIDEB that were identified by exome sequencing and included in the gene burden association analyses Genomic coordinates for the Variant AAF, genetic variant, classified fraction C:P:R:A Coding DNA change Protein change as pLOF of 1 14:24305640:G:A c.653C > T, c.653C > T, c.653C > T p.Ser218Phe, p.Ser218Phe, p.Ser218Phe No 4.0E−05 14:24305643:T:C c.650A > G, c.650A > G, c.650A > G p.His217Arg, p.His217Arg, p.His217Arg No 1.7E−05 14:24305649:C:T c.644G > A, c.644G > A, c.644G > A p.Arg215His, p.Arg215His, p.Arg215His No 1.2E−05 14:24305650:G:A c.643C > T, c.643C > T, c.643C > T p.Arg215Cys, p.Arg215Cys, p.Arg215Cys No 1.1E−05 14:24305650:G:C c.643C > G, c.643C > G, c.643C > G p.Arg215Gly, p.Arg215Gly, p.Arg215Gly No 3.8E−05 14:24305658:T:G c.635A > C, c.635A > C, c.635A > C p.Gln212Pro, p.Gln212Pro, p.Gln212Pro No 1.1E−05 14:24305664:C:T c.629G > A, c.629G > A, c.629G > A p.Trp210*, p.Trp210*, p.Trp210* Yes 1.1E−05 14:24305667:T:C c.626A > G, c.626A > G, c.626A > G p.Gln209Arg, p.Gln209Arg, p.Gln209Arg No 4.3E−06 14:24305671:C:T c.622G > A, c.622G > A, c.622G > A p.Glu208Lys, p.Glu208Lys, p.Glu208Lys No 5.8E−04 14:24305683:C:G c.610G > C, c.610G > C, c.610G > C p.Val204Leu, p.Val204Leu, p.Val204Leu No 5.8E−06 14:24305686:C:G c.607G > C, c.607G > C, c.607G > C p.Ala203Pro, p.Ala203Pro, p.Ala203Pro No 1.1E−04 14:24305691:C:T c.602G > A, c.602G > A, c.602G > A p.Arg201His, p.Arg201His, p.Arg201His No 2.9E−05 14:24305718:A:G c.575T > C, c.575T > C, c.575T > C p.Met192Thr, p.Met192Thr, p.Met192Thr No 1.4E−05 14:24305721:T:C c.572A > G, c.572A > G, c.572A > G p.His191Arg, p.His191Arg, p.His191Arg No 3.3E−05 14:24305733:T:C c.560A > G, c.560A > G, c.560A > G p.Gln187Arg, p.Gln187Arg, p.Gln187Arg No 2.0E−05 14:24305755:G:A c.538C > T, c.538C > T, c.538C > T p.Arg180Cys, p.Arg180Cys, p.Arg180Cys No 9.7E−05 14:24305766:C:T c.528 − 1G > A, Yes 9.3E−06 c.528 − 1G > A, c.528 − 1G > A 14:24305946:C:T c.527 + 1G > A, Yes 5.8E−05 c.527 + 1G > A, c.527 + 1G > A 14:24305953:A:G c.521T > C, c.521T > C, c.521T > C p.Val174Ala, p.Val174Ala, p.Val174Ala No 1.5E−05 14:24305963:G:A c.511C > T, c.511C > T, c.511C > T p.Pro171Ser, p.Pro171Ser, p.Pro171Ser No 4.5E−06 14:24305966:C:T c.508G > A, c.508G > A, c.508G > A p.Gly170Ser, p.Gly170Ser, p.Gly170Ser No 4.5E−06 14:24305972:C:G c.502G > C, c.502G > C, c.502G > C p.Gly168Arg, p.Gly168Arg, p.Gly168Arg No 7.8E−06 14:24305988:CAT:C c.484_485delAT, p.Met162fs, p.Met162fs, p.Met162fs Yes 2.8E−05 c.484_485delAT, c.484_485delAT 14:24305990:T:C c.484A > G, c.484A > G, c.484A > G p.Met162Val, p.Met162Val, p.Met162Val No 5.8E−06 14:24306002:C:T c.472G > A, c.472G > A, c.472G > A p.Gly158Arg, p.Gly158Arg, p.Gly158Arg No 1.7E−05 14:24306017:T:A c.457A > T, c.457A > T, c.457A > T p.Lys153*, p.Lys153*, p.Lys153* Yes 5.5E−05 14:24306041:C:G c.433G > C, c.433G > C, c.433G > C p.Asp145His, p.Asp145His, p.Asp145His No 4.3E−06 14:24306047:G:A c.427C > T, c.427C > T, c.427C > T p.Pro143Ser, p.Pro143Ser, p.Pro143Ser No 4.7E−05 14:24306052:TG:T c.421delC, c.421delC, c.421delC p.Gln141fs, p.Gln141fs, p.Gln141fs Yes 2.3E−05 14:24306062:C:A c.412G > T, c.412G > T, c.412G > T p.Val138Leu, p.Val138Leu, p.Val138Leu No 3.5E−05 14:24306062:C:T c.412G > A, c.412G > A, c.412G > A p.Val138Met, p.Val138Met, p.Val138Met No 4.9E−05 14:24306076:C:T c.398G > A, c.398G > A, c.398G > A p.Arg133Gln, p.Arg133Gln, p.Arg133Gln No 1.7E−05 14:24306077:G:A c.397C > T, c.397C > T, c.397C > T p.Arg133*, p.Arg133*, p.Arg133* Yes 2.7E−05 14:24306082:A:G c.392T > C, c.392T > C, c.392T > C p.Ile131Thr, p.Ile131Thr, p.Ile131Thr No 8.9E−06 14:24306095:G:A c.379C > T, c.379C > T, c.379C > T p.His127Tyr, p.His127Tyr, p.His127Tyr No 7.2E−06 14:24306109:C:T c.365G > A, c.365G > A, c.365G > A p.Arg122Gln, p.Arg122Gln, p.Arg122Gln No 7.5E−06 14:24306110:G:A c.364C > T, c.364C > T, c.364C > T p.Arg122Trp, p.Arg122Trp, p.Arg122Trp No 4.0E−04 14:24306131:C:T c.343G > A, c.343G > A, c.343G > A p.Val115Met, p.Val115Met, p.Val115Met No 2.1E−05 14:24306373:C:T c.336 + 1G > A, Yes 4.1E−04 c.336 + 1G > A, c.336 + 1G > A 14:24306379:T:C c.331A > G, c.331A > G, c.331A > G p.Thr111Ala, p.Thr111Ala, p.Thr111Ala No 3.6E−05 14:24306383:G:C c.327C > G, c.327C > G, c.327C > G p.Ser109Arg, p.Ser109Arg, p.Ser109Arg No 1.3E−05 14:24306403:G:A c.307C > T, c.307C > T, c.307C > T p.Gln103*, p.Gln103*, p.Gln103* Yes 1.4E−05 14:24306410:C:T c.300G > A, c.300G > A, c.300G > A p.Met100Ile, p.Met100Ile, p.Met100Ile No 3.2E−05 14:24306417:C:T c.293G > A, c.293G > A, c.293G > A p.Cys98Tyr, p.Cys98Tyr, p.Cys98Tyr No 1.8E−05 14:24306420:G:C c.290C > G, c.290C > G, c.290C > G p.Thr97Arg, p.Thr97Arg, p.Thr97Arg No 1.1E−05 14:24306420:G:A c.290C > T, c.290C > T, c.290C > T p.Thr97Met, p.Thr97Met, p.Thr97Met No 6.4E−04 14:24306423:T:G c.287A > C, c.287A > C, c.287A > C p.Asp96Ala, p.Asp96Ala, p.Asp96Ala No 5.2E−05 14:24306437:C:G c.273G > C, c.273G > C, c.273G > C p.Gln91His, p.Gln91His, p.Gln91His No 5.2E−06 14:24306442:A:G c.268T > C, c.268T > C, c.268T > C p.Phe90Leu, p.Phe90Leu, p.Phe90Leu No 4.7E−06 14:24306451:C:T c.259G > A, c.259G > A, c.259G > A p.Glu87Lys, p.Glu87Lys, p.Glu87Lys No 5.6E−05 14:24306463:C:T c.247G > A, c.247G > A, c.247G > A p.Ala83Thr, p.Ala83Thr, p.Ala83Thr No 1.2E−04 14:24306483:A:G c.227T > C, c.227T > C, c.227T > C p.Val76Ala, p.Val76Ala, p.Val76Ala No 2.2E−05 14:24306486:A:C c.224T > G, c.224T > G, c.224T > G p.Leu75Arg, p.Leu75Arg, p.Leu75Arg No 1.5E−05 14:24306504:A:G c.206T > C, c.206T > C, c.206T > C p.Leu69Pro, p.Leu69Pro, p.Leu69Pro No 5.3E−06 14:24307385:C:T c.172G > A, c.172G > A, c.172G > A p.Glu58Lys, p.Glu58Lys, p.Glu58Lys No 3.1E−05 14:24307390:C:T c.167G > A, c.167G > A, c.167G > A p.Arg56His, p.Arg56His, p.Arg56His No 1.0E−05 14:24307411:T:C c.146A > G, c.146A > G, c.146A > G p.Lys49Arg, p.Lys49Arg, p.Lys49Arg No 2.8E−05 14:24307423:C:T c.134G > A, c.134G > A, c.134G > A p.Arg45Gln, p.Arg45Gln, p.Arg45Gln No 1.1E−05 14:24307424:G:A c.133C > T, c.133C > T, c.133C > T p.Arg45Trp, p.Arg45Trp, p.Arg45Trp No 6.1E−05 14:24307442:G:A c.115C > T, c.115C > T, c.115C > T p.Arg39Cys, p.Arg39Cys, p.Arg39Cys No 1.0E−04 14:24307447:G:A c.110C > T, c.110C > T, c.110C > T p.Pro37Leu, p.Pro37Leu, p.Pro37Leu No 8.3E−06 14:24307451:G:A c.106C > T, c.106C > T, c.106C > T p.Arg36*, p.Arg36*, p.Arg36* Yes 3.4E−05 14:24307461:TG:T c.95delC, c.95delC, c.95delC p.Pro32fs, p.Pro32fs, p.Pro32fs Yes 1.3E−05 14:24307469:AG:A c.87delC, c.87delC, c.87delC p.Ser30fs, p.Ser30fs, p.Ser30fs Yes 1.7E−05 14:24307474:C:T c.83G > A, c.83G > A, c.83G > A p.Trp28*, p.Trp28*, p.Trp28* Yes 5.3E−06 14:24307483:C:T c.74G > A, c.74G > A, c.74G > A p.Arg25Gln, p.Arg25Gln, p.Arg25Gln No 3.4E−05 14:24307484:G:A c.73C > T, c.73C > T, c.73C > T p.Arg25Trp, p.Arg25Trp, p.Arg25Trp No 2.9E−05 14:24307495:G:A c.62C > T, c.62C > T, c.62C > T p.Ser21Leu, p.Ser21Leu, p.Ser21Leu No 1.3E−05 14:24307498:C:T c.59G > A, c.59G > A, c.59G > A p.Ser20Asn, p.Ser20Asn, p.Ser20Asn No 7.6E−05 14:24307825:A:C c.34T > G, c.34T > G, c.34T > G p.Leu12Val, p.Leu12Val, p.Leu12Val No 7.1E−05 14:24307829:A:C c.30T > G, c.30T > G, c.30T > G p.Ser10Arg, p.Ser10Arg, p.Ser10Arg No 4.7E−06 14:24307839:A:C c.20T > G, c.20T > G, c.20T > G p.Leu7Arg, p.Leu7Arg, p.Leu7Arg No 7.6E−06 14:24305635:A:AGTAG c.654_657dupCTAC, p.Ter220fs, p.Ter220fs, p.Ter220fs Yes 3.2E−06 c.654_657dupCTAC, c.654_657dupCTAC 14:24305641:A:C c.652T > G, c.652T > G, c.652T > G p.Ser218Ala, p.Ser218Ala, p.Ser218Ala No 1.2E−05 14:24305662:G:T c.631C > A, c.631C > A, c.631C > A p.Gln211Lys, p.Gln211Lys, p.Gln211Lys No 3.9E−06 14:24305677:C:G c.616G > C, c.616G > C, c.616G > C p.Gly206Arg, p.Gly206Arg, p.Gly206Arg No 6.7E−06 14:24305692:G:A c.601C > T, c.601C > T, c.601C > T p.Arg201Cys, p.Arg201Cys, p.Arg201Cys No 6.0E−06 14:24305701:A:T c.592T > A, c.592T > A, c.592T > A p.Ser198Thr, p.Ser198Thr, p.Ser198Thr No 3.2E−06 14:24305728:G:GGCCTT c.560_564dupAAGGC, p.Leu189fs, p.Leu189fs, p.Leu189fs Yes 3.7E−06 c.560_564dupAAGGC, c.560_564dupAAGGC 14:24305743:T:C c.550A > G, c.550A > G, c.550A > G p.Thr184Ala, p.Thr184Ala, p.Thr184Ala No 3.2E−06 14:24305754:C:T c.539G > A, c.539G > A, c.539G > A p.Arg180His, p.Arg180His, p.Arg180His No 8.6E−06 14:24305948:T:C c.526A > G, c.526A > G, c.526A > G p.Arg176Gly, p.Arg176Gly, p.Arg176Gly No 3.2E−06 14:24305953:ACTTT:A c.517_520delAAAG, p.Lys173fs, p.Lys173fs, p.Lys173fs Yes 1.5E−05 c.517_520delAAAG, c.517_520delAAAG 14:24306014:C:T c.460G > A, c.460G > A, c.460G > A p.Ala154Thr, p.Ala154Thr, p.Ala154Thr No 3.4E−06 14:24306044:G:A c.430C > T, c.430C > T, c.430C > T p.Arg144*, p.Arg144*, p.Arg144* Yes 2.3E−05 14:24306064:T:C c.410A > G, c.410A > G, c.410A > G p.Asp137Gly, p.Asp137Gly, p.Asp137Gly No 3.2E−06 14:24306080:C:T c.394G > A, c.394G > A, c.394G > A p.Ala132Thr, p.Ala132Thr, p.Ala132Thr No 4.3E−05 14:24306083:T:A c.391A > T, c.391A > T, c.391A > T p.Ile131Phe, p.Ile131Phe, p.Ile131Phe No 3.2E−06 14:24306087:C:G c.387G > C, c.387G > C, c.387G > C p.Lys129Asn, p.Lys129Asn, p.Lys129Asn No 4.5E−06 14:24306095:G:T c.379C > A, c.379C > A, c.379C > A p.His127Asn, p.His127Asn, p.His127Asn No 1.5E−05 14:24306134:C:G c.340G > C, c.340G > C, c.340G > C p.Gly114Arg, p.Gly114Arg, p.Gly114Arg No 3.4E−06 14:24306138:CTG:C c.337 − 3_337 − 2delCA, Yes 8.0E−06 c.337 − 3_337 − 2delCA, c.337 − 3_337 − 2delCA 14:24306139:T:C c.337 − 2A > G, Yes 2.1E−05 c.337 − 2A > G, c.337 − 2A > G 14:24306373:C:A c.336 + 1G > T, Yes 1.3E−05 c.336 + 1G > T, c.336 + 1G > T 14:24306382:G:A c.328C > T, c.328C > T, c.328C > T p.Pro110Ser, p.Pro110Ser, p.Pro110Ser No 3.2E−06 14:24306387:C:T c.323G > A, c.323G > A, c.323G > A p.Trp108*, p.Trp108*, p.Trp108* Yes 4.5E−06 14:24306418:A:G c.292T > C, c.292T > C, c.292T > C p.Cys98Arg, p.Cys98Arg, p.Cys98Arg No 8.4E−06 14:24306433:G:GA c.276_277insT, p.Leu93fs, p.Leu93fs, p.Leu93fs Yes 5.4E−06 c.276_277insT, c.276_277insT 14:24306439:G:C c.271C > G, c.271C > G, c.271C > G p.Gln91Glu, p.Gln91Glu, p.Gln91Glu No 3.2E−06 14:24306444:A:G c.266T > C, c.266T > C, c.266T > C p.Phe89Ser, p.Phe89Ser, p.Phe89Ser No 3.2E−06 14:24306469:C:T c.241G > A, c.241G > A, c.241G > A p.Gly81Arg, p.Gly81Arg, p.Gly81Arg No 3.7E−06 14:24306480:A:G c.230T > C, c.230T > C, c.230T > C p.Leu77Pro, p.Leu77Pro, p.Leu77Pro No 3.2E−06 14:24306508:G:C c.202C > G, c.202C > G, c.202C > G p.Leu68Val, p.Leu68Val, p.Leu68Val No 5.6E−06 14:24306511:G:T c.199C > A, c.199C > A, c.199C > A p.Leu67Ile, p.Leu67Ile, p.Leu67Ile No 3.2E−06 14:24307382:G:C c.175C > G, c.175C > G, c.175C > G p.Leu59Val, p.Leu59Val, p.Leu59Val No 3.2E−06 14:24307391:G:A c.166C > T, c.166C > T, c.166C > T p.Arg56Cys, p.Arg56Cys, p.Arg56Cys No 5.2E−06 14:24307402:G:A c.155C > T, c.155C > T, c.155C > T p.Thr52Ile, p.Thr52Ile, p.Thr52Ile No 1.4E−05 14:24307405:A:G c.152T > C, c.152T > C, c.152T > C p.Leu51Pro, p.Leu51Pro, p.Leu51Pro No 6.2E−06 14:24307421:T:A c.136A > T, c.136A > T, c.136A > T p.Thr46Ser, p.Thr46Ser, p.Thr46Ser No 3.2E−06 14:24307441:C:A c.116G > T, c.116G > T, c.116G > T p.Arg39Leu, p.Arg39Leu, p.Arg39Leu No 3.2E−06 14:24307441:C:T c.116G > A, c.116G > A, c.116G > A p.Arg39His, p.Arg39His, p.Arg39His No 3.9E−05 14:24307448:G:T c.109C > A, c.109C > A, c.109C > A p.Pro37Thr, p.Pro37Thr, p.Pro37Thr No 3.3E−05 14:24307450:C:T c.107G > A, c.107G > A, c.107G > A p.Arg36Gln, p.Arg36Gln, p.Arg36Gln No 1.9E−05 14:24307475:A:G c.82T > C, c.82T > C, c.82T > C p.Trp28Arg, p.Trp28Arg, p.Trp28Arg No 6.4E−06 14:24307510:A:T c.47T > A, c.47T > A, c.47T > A p.Val16Glu, p.Val16Glu, p.Val16Glu No 4.1E−06 14:24307516:C:G c.42 − 1G > C, Yes 1.2E−05 c.42 − 1G > C, c.42 − 1G > C 14:24307822:G:GT c.36dupA, c.36dupA, c.36dupA p.Leu13fs, p.Leu13fs, p.Leu13fs Yes 4.1E−06 14:24307824:A:T c.35T > A, c.35T > A, c.35T > A p.Leu12*, p.Leu12*, p.Leu12* Yes 3.9E−06 14:24307833:G:C c.26C > G, c.26C > G, c.26C > G p.Pro9Arg, p.Pro9Arg, p.Pro9Arg No 3.2E−06 14:24307851:T:TAC c.6_7dupGT, c.6_7dupGT, c.6_7dupGT p.Tyr3fs, p.Tyr3fs, p.Tyr3fs Yes 7.5E−06 14:24307857:A:C c.2T > G, c.2T > G, c.2T > G p.Met1?, p.Met1?, p.Met1? Yes 2.0E−05 14:24305635:A:C c.658T > G, c.658T > G, c.658T > G p.Ter220Gluext*?, Yes 8.7E−07 p.Ter220Gluext*?, p.Ter220Gluext*? 14:24305637:T:C c.656A > G, c.656A > G, c.656A > G p.Tyr219Cys, p.Tyr219Cys, p.Tyr219Cys No 6.1E−06 14:24305638:A:G c.655T > C, c.655T > C, c.655T > C p.Tyr219His, p.Tyr219His, p.Tyr219His No 8.7E−07 14:24305652:C:T c.641G > A, c.641G > A, c.641G > A p.Gly214Asp, p.Gly214Asp, p.Gly214Asp No 4.3E−07 14:24305653:C:T c.640G > A, c.640G > A, c.640G > A p.Gly214Ser, p.Gly214Ser, p.Gly214Ser No 1.3E−06 14:24305657:C:A c.636G > T, c.636G > T, c.636G > T p.Gln212His, p.Gln212His, p.Gln212His No 4.3E−07 14:24305657:C:G c.636G > C, c.636G > C, c.636G > C p.Gln212His, p.Gln212His, p.Gln212His No 8.7E−07 14:24305660:C:G c.633G > C, c.633G > C, c.633G > C p.Gln211His, p.Gln211His, p.Gln211His No 4.3E−07 14:24305661:T:G c.632A > C, c.632A > C, c.632A > C p.Gln211Pro, p.Gln211Pro, p.Gln211Pro No 4.3E−07 14:24305661:T:C c.632A > G, c.632A > G, c.632A > G p.Gln211Arg, p.Gln211Arg, p.Gln211Arg No 4.3E−07 14:24305663:C:G c.630G > C, c.630G > C, c.630G > C p.Trp210Cys, p.Trp210Cys, p.Trp210Cys No 1.7E−06 14:24305663:C:T c.630G > A, c.630G > A, c.630G > A p.Trp210*, p.Trp210*, p.Trp210* Yes 8.7E−07 14:24305668:G:A c.625C > T, c.625C > T, c.625C > T p.Gln209*, p.Gln209*, p.Gln209* Yes 4.3E−07 14:24305671:C:A c.622G > T, c.622G > T, c.622G > T p.Glu208*, p.Glu208*, p.Glu208* Yes 4.3E−07 14:24305671:C:G c.622G > C, c.622G > C, c.622G > C p.Glu208Gln, p.Glu208Gln, p.Glu208Gln No 4.3E−07 14:24305673:G:A c.620C > T, c.620C > T, c.620C > T p.Ala207Val, p.Ala207Val, p.Ala207Val No 1.7E−06 14:24305674:C:T c.619G > A, c.619G > A, c.619G > A p.Ala207Thr, p.Ala207Thr, p.Ala207Thr No 4.3E−07 14:24305676:C:T c.617G > A, c.617G > A, c.617G > A p.Gly206Glu, p.Gly206Glu, p.Gly206Glu No 4.3E−07 14:24305678:C:G c.615G > C, c.615G > C, c.615G > C p.Glu205Asp, p.Glu205Asp, p.Glu205Asp No 4.3E−07 14:24305678:C:A c.615G > T, c.615G > T, c.615G > T p.Glu205Asp, p.Glu205Asp, p.Glu205Asp No 4.3E−07 14:24305679:T:C c.614A > G, c.614A > G, c.614A > G p.Glu205Gly, p.Glu205Gly, p.Glu205Gly No 4.3E−07 14:24305680:C:G c.613G > C, c.613G > C, c.613G > C p.Glu205Gln, p.Glu205Gln, p.Glu205Gln No 4.3E−07 14:24305682:A:C c.611T > G, c.611T > G, c.611T > G p.Val204Gly, p.Val204Gly, p.Val204Gly No 8.7E−07 14:24305685:G:T c.608C > A, c.608C > A, c.608C > A p.Ala203Glu, p.Ala203Glu, p.Ala203Glu No 4.3E−07 14:24305685:G:C c.608C > G, c.608C > G, c.608C > G p.Ala203Gly, p.Ala203Gly, p.Ala203Gly No 2.6E−06 14:24305688:T:G c.605A > C, c.605A > C, c.605A > C p.His202Pro, p.His202Pro, p.His202Pro No 4.3E−07 14:24305695:G:C c.598C > G, c.598C > G, c.598C > G p.Leu200Val, p.Leu200Val, p.Leu200Val No 4.3E−07 14:24305695:G:T c.598C > A, c.598C > A, c.598C > A p.Leu200Ile, p.Leu200Ile, p.Leu200Ile No 1.3E−06 14:24305697:G:C c.596C > G, c.596C > G, c.596C > G p.Thr199Ser, p.Thr199Ser, p.Thr199Ser No 4.3E−07 14:24305706:A:G c.587T > C, c.587T > C, c.587T > C p.Ile196Thr, p.Ile196Thr, p.Ile196Thr No 4.3E−07 14:24305709:C:T c.584G > A, c.584G > A, c.584G > A p.Gly195Glu, p.Gly195Glu, p.Gly195Glu No 4.3E−07 14:24305710:C:T c.583G > A, c.583G > A, c.583G > A p.Gly195Arg, p.Gly195Arg, p.Gly195Arg No 1.7E−06 14:24305721:T:A c.572A > T, c.572A > T, c.572A > T p.His191Leu, p.His191Leu, p.His191Leu No 8.7E−07 14:24305722:G:C c.571C > G, c.571C > G, c.571C > G p.His191Asp, p.His191Asp, p.His191Asp No 4.3E−07 14:24305727:A:C c.566T > G, c.566T > G, c.566T > G p.Leu189Arg, p.Leu189Arg, p.Leu189Arg No 4.3E−07 14:24305730:C:A c.563G > T, c.563G > T, c.563G > T p.Gly188Val, p.Gly188Val, p.Gly188Val No 4.3E−07 14:24305748:G:T c.545C > A, c.545C > A, c.545C > A p.Thr182Asn, p.Thr182Asn, p.Thr182Asn No 4.3E−07 14:24305748:G:C c.545C > G, c.545C > G, c.545C > G p.Thr182Ser, p.Thr182Ser, p.Thr182Ser No 4.3E−07 14:24305749:T:C c.544A > G, c.544A > G, c.544A > G p.Thr182Ala, p.Thr182Ala, p.Thr182Ala No 4.3E−07 14:24305752:A:G c.541T > C, c.541T > C, c.541T > C p.Trp181Arg, p.Trp181Arg, p.Trp181Arg No 4.3E−07 14:24305754:C:A c.539G > T, c.539G > T, c.539G > T p.Arg180Leu, p.Arg180Leu, p.Arg180Leu No 8.7E−07 14:24305758:G:C c.535C > G, c.535C > G, c.535C > G p.Leu179Val, p.Leu179Val, p.Leu179Val No 4.3E−07 14:24305761:G:A c.532C > T, c.532C > T, c.532C > T p.Leu178Phe, p.Leu178Phe, p.Leu178Phe No 4.3E−07 14:24305763:T:G c.530A > C, c.530A > C, c.530A > C p.Glu177Ala, p.Glu177Ala, p.Glu177Ala No 4.3E−07 14:24305766:C:A c.528 − 1G > T, c.528 − 1G > Yes 4.3E−07 T, c.528 − 1G > T 14:24305766:C:G c.528 − 1G > C, c.528 − 1G > Yes 7.8E−06 C, c.528 − 1G > C 14:24305767:T:G c.528 − 2A > C, c.528 − 2A > Yes 4.3E−07 C, c.528 − 2A > C 14:24305946:C:A c.527 + 1G > T, Yes 7.4E−06 c.527 + 1G > T, c.527 + 1G > T 14:24305950:A:C c.524T > G, c.524T > G, c.524T > G p.Leu175Arg, p.Leu175Arg, p.Leu175Arg No 8.7E−07 14:24305951:G:A c.523C > T, c.523C > T, c.523C > T p.Leu175Phe, p.Leu175Phe, p.Leu175Phe No 4.3E−07 14:24305953:AC:A c.520delG, c.520delG, c.520delG p.Val174fs, p.Val174fs, p.Val174fs Yes 8.7E−07 14:24305954:C:CT c.519dupA, c.519dupA, c.519dupA p.Val174fs, p.Val174fs, p.Val174fs Yes 4.3E−07 14:24305957:T:A c.517A > T, c.517A > T, c.517A > T p.Lys173*, p.Lys173*, p.Lys173* Yes 4.3E−07 14:24305958:C:A c.516G > T, c.516G > T, c.516G > T p.Lys172Asn, p.Lys172Asn, p.Lys172Asn No 4.3E−07 14:24305958:C:G c.516G > C, c.516G > C, c.516G > C p.Lys172Asn, p.Lys172Asn, p.Lys172Asn No 4.3E−07 14:24305961:TG:T c.512delC, c.512delC, c.512delC p.Pro171fs, p.Pro171fs, p.Pro171fs Yes 4.3E−07 14:24305963:G:T c.511C > A, c.511C > A, c.511C > A p.Pro171Thr, p.Pro171Thr, p.Pro171Thr No 4.3E−07 14:24305965:C:T c.509G > A, c.509G > A, c.509G > A p.Gly170Asp, p.Gly170Asp, p.Gly170Asp No 1.7E−06 14:24305966:C:A c.508G > T, c.508G > T, c.508G > T p.Gly170Cys, p.Gly170Cys, p.Gly170Cys No 4.3E−07 14:24305968:A:C c.506T > G, c.506T > G, c.506T > G p.Leu169Arg, p.Leu169Arg, p.Leul69Arg No 1.4E−05 14:24305968:A:T c.506T > A, c.506T > A, c.506T > A p.Leu169His, p.Leu169His, p.Leu169His No 4.3E−07 14:24305968:A:G c.506T > C, c.506T > C, c.506T > C p.Leu169Pro, p.Leu169Pro, p.Leu169Pro No 4.3E−07 14:24305971:C:G c.503G > C, c.503G > C, c.503G > C p.Gly168Ala, p.Gly168Ala, p.Gly168Ala No 4.3E−07 14:24305974:T:TG c.499dupC, c.499dupC, c.499dupC p.Gln167fs, p.Gln167fs, p.Gln16fs Yes 6.5E−06 14:24305974:T:C c.500A > G, c.500A > G, c.500A > G p.Gln167Arg, p.Gln167Arg, p.Gln167Arg No 8.7E−07 14:24305980:T:A c.494A > T, c.494A > T, c.494A > T p.Asp165Val, p.Asp165Val, p.Asp165Val No 4.3E−07 14:24305980:TCA:T c.492_493delTG, p.Cys164fs, p.Cys164fs, p.Cys164fs Yes 1.3E−06 c.492_493delTG, c.492_493delTG 14:24305982:A:C c.492T > G, c.492T > G, c.492T > G p.Cys164Trp, p.Cys164Trp, p.Cys164Trp No 1.3E−06 14:24305986:C:G c.488G > C, c.488G > C, c.488G > C p.Ser163Thr, p.Ser163Thr, p.Ser163Thr No 4.3E−07 14:24305986:C:T c.488G > A, c.488G > A, c.488G > A p.Ser163Asn, p.Ser163Asn, p.Ser163Asn No 8.7E−07 14:24305988:CATAGA:C c.481_485delTCTAT, p.Ser161fs, p.Ser161fs, p.Ser161fs Yes 4.3E−07 c.481_485delTCTAT, c.481_485delTCTAT 14:24305988:C:T c.486G > A, c.486G > A, c.486G > A p.Met162Ile, p.Met162Ile, p.Met162Ile No 1.3E−06 14:24305989:A:G c.485T > C, c.485T > C, c.485T > C p.Met162Thr, p.Met162Thr, p.Met162Thr No 2.6E−06 14:24305990:T:A c.484A > T, c.484A > T, c.484A > T p.Met162Leu, p.Met162Leu, p.Met162Leu No 4.3E−07 14:24305992:G:A c.482C > T, c.482C > T, c.482C > T p.Ser161Phe, p.Ser161Phe, p.Ser161Phe No 4.3E−07 14:24305995:T:C c.479A > G, c.479A > G, c.479A > G p.Tyr160Cys, p.Tyr160Cys, p.Tyr160Cys No 1.3E−06 14:24305998:A:G c.476T > C, c.476T > C, c.476T > C p.Leu159Pro, p.Leu159Pro, p.Leu159Pro No 8.7E−07 14:24305999:G:A c.475C > T, c.475C > T, c.475C > T p.Leu159Phe, p.Leu159Phe, p.Leu159Phe No 8.7E−07 14:24306001:C:T c.473G > A, c.473G > A, c.473G > A p.Gly158Glu, p.Gly158Glu, p.Gly158Glu No 8.7E−07 14:24306003:G:T c.471C > A, c.471C > A, c.471C > A p.Tyr157*, p.Tyr157*, p.Tyr157* Yes 1.3E−06 14:24306005:A:C c.469T > G, c.469T > G, c.469T > G p.Tyr157Asp, p.Tyr157Asp, p.Tyr157Asp No 4.3E−07 14:24306006:G:C c.468C > G, c.468C > G, c.468C > G p.Phe156Leu, p.Phe156Leu, p.Phe156Leu No 4.3E−07 14:24306008:A:G c.466T > C, c.466T > C, c.466T > C p.Phe156Leu, p.Phe156Leu, p.Phe156Leu No 4.3E−07 14:24306010:G:A c.464C > T, c.464C > T, c.464C > T p.Thr155Ile, p.Thr155Ile, p.Thr155Ile No 4.3E−07 14:24306013:G:A c.461C > T, c.461C > T, c.461C > T p.Ala154Val, p.Ala154Val, p.Ala154Val No 4.3E−07 14:24306016:T:C c.458A > G, c.458A > G, c.458A > G p.Lys153Arg, p.Lys153Arg, p.Lys153Arg No 2.6E−06 14:24306020:C:T c.454G > A, c.454G > A, c.454G > A p.Val152Ile, p.Val152Ile, p.Val152Ile No 8.7E−07 14:24306027:G:C c.447C > G, c.447C > G, c.447C > G p.Ser149Arg, p.Ser149Arg, p.Ser149Arg No 4.3E−07 14:24306028:CT:C c.445delA, c.445delA, c.445delA p.Ser149fs, p.Ser149fs, p.Ser149fs Yes 4.3E−07 14:24306031:C:T c.443G > A, c.443G > A, c.443G > A p.Gly148Asp, p.Gly148Asp, p.Gly148Asp No 4.3E−07 14:24306032:C:T c.442G > A, c.442G > A, c.442G > A p.Gly148Ser, p.Gly148Ser, p.Gly148Ser No 2.2E−06 14:24306034:A:C c.440T > G, c.440T > G, c.440T > G p.Phe147Cys, p.Phe147Cys, p.Phe147Cys No 4.3E−07 14:24306034:A:T c.440T > A, c.440T > A, c.440T > A p.Phe147Tyr, p.Phe147Tyr, p.Phe147Tyr No 4.3E−07 14:24306034:A:G c.440T > C, c.440T > C, c.440T > C p.Phe147Ser, p.Phe147Ser, p.Phe147Ser No 4.3E−07 14:24306039:G:C c.435C > G, c.435C > G, c.435C > G p.Asp145Glu, p.Asp145Glu, p.Asp145Glu No 2.2E−06 14:24306039:G:T c.435C > A, c.435C > A, c.435C > A p.Asp145Glu, p.Asp145Glu, p.Asp145Glu No 8.7E−07 14:24306041:C:T c.433G > A, c.433G > A, c.433G > A p.Asp145Asn, p.Asp145Asn, p.Asp145Asn No 8.7E−07 14:24306043:C:A c.431G > T, c.431G > T, c.431G > T p.Arg144Leu, p.Arg144Leu, p.Arg144Leu No 8.7E−07 14:24306043:C:T c.431G > A, c.431G > A, c.431G > A p.Arg144Gln, p.Arg144Gln, p.Arg144Gln No 4.3E−06 14:24306043:C:G c.431G > C, c.431G > C, c.431G > C p.Arg144Pro, p.Arg144Pro, p.Arg144Pro No 1.7E−06 14:24306044:G:C c.430C > G, c.430C > G, c.430C > G p.Arg144Gly, p.Arg144Gly, p.Arg144Gly No 2.6E−06 14:24306046:G:A c.428C > T, c.428C > T, c.428C > T p.Pro143Leu, p.Pro143Leu, p.Pro143Leu No 4.3E−07 14:24306047:G:T c.427C > A, c.427C > A, c.427C > A p.Pro143Thr, p.Pro143Thr, p.Pro143Thr No 4.3E−07 14:24306051:T:G c.423A > C, c.423A > C, c.423A > C p.Gln141His, p.Gln141His, p.Gln141His No 4.3E−07 14:24306057:G:C c.417C > G, c.417C > G, c.417C > G p.Tyr139*, p.Tyr139*, p.Tyrl39* Yes 4.3E−07 14:24306057:G:T c.417C > A, c.417C > A, c.417C > A p.Tyr139*, p.Tyr139*, p.Tyr139* Yes 4.3E−07 14:24306058:T:C c.416A > G, c.416A > G, c.416A > G p.Tyr139Cys, p.Tyr139Cys, p.Tyr139Cys No 1.3E−06 14:24306059:AC:A c.414delG, c.414delG, c.414delG p.Tyr139fs, p.Tyr139fs, p.Tyr139fs Yes 4.3E−07 14:24306061:AC:A c.412delG, c.412delG, c.412delG p.Val138fs, p.Val138fs, p.Val138fs Yes 4.3E−07 14:24306062:CGTCAAAG:C c.405_411delCTTTGAC, p.Phe136fs, p.Phe136fs, p.Phe136fs Yes 8.7E−07 c.405_411delCTTTGAC, c.405_411delCTTTGAC 14:24306063:G:T c.411C > A, c.411C > A, c.411C > A p.Asp137Glu, p.Asp137Glu, p.Asp137Glu No 2.2E−06 14:24306064:T:G c.410A > C, c.410A > C, c.410A > C p.Asp137Ala, p.Asp137Ala, p.Asp137Ala No 4.3E−07 14:24306065:C:G c.409G > C, c.409G > C, c.409G > C p.Asp137His, p.Asp137His, p.Asp137His No 8.7E−07 14:24306066:A:C c.408T > G, c.408T > G, c.408T > G p.Phe136Leu, p.Phe136Leu, p.Phe136Leu No 4.3E−07 14:24306070:G:A c.404C > T, c.404C > T, c.404C > T p.Thr135Ile, p.Thr135Ile, p.Thr135Ile No 1.3E−06 14:24306072:G:T c.402C > A, c.402C > A, c.402C > A p.Phe134Leu, p.Phe134Leu, p.Phe134Leu No 4.3E−07 14:24306074:A:T c.400T > A, c.400T > A, c.400T > A p.Phe134Ile, p.Phe134Ile, p.Phe134Ile No 8.7E−07 14:24306074:A:G c.400T > C, c.400T > C, c.400T > C p.Phe134Leu, p.Phe134Leu, p.Phe134Leu No 4.3E−07 14:24306077:G:C c.397C > G, c.397C > G, c.397C > G p.Arg133Gly, p.Arg133Gly, p.Arg133Gly No 4.3E−07 14:24306083:T:C c.391A > G, c.391A > G, c.391A > G p.Ile131Val, p.Ile131Val, p.Ile131Val No 4.3E−07 14:24306086:C:T c.388G > A, c.388G > A, c.388G > A p.Asp130Asn, p.Asp130Asn, p.Asp130Asn No 1.3E−06 14:24306089:T:G c.385A > C, c.385A > C, c.385A > C p.Lys129Gln, p.Lys129Gln, p.Lys129Gln No 4.3E−07 14:24306092:T:A c.382A > T, c.382A > T, c.382A > T p.Ser128Cys, p.Ser128Cys, p.Ser128Cys No 4.3E−07 14:24306092:T:C c.382A > G, c.382A > G, c.382A > G p.Ser128Gly, p.Ser128Gly, p.Ser128Gly No 1.3E−06 14:24306092:T:G c.382A > C, c.382A > C, c.382A > C p.Ser128Arg, p.Ser128Arg, p.Ser128Arg No 4.3E−07 14:24306097:T:C c.377A > G, c.377A > G, c.377A > G p.Lys126Arg, p.Lys126Arg, p.Lys126Arg No 1.3E−06 14:24306098:T:C c.376A > G, c.376A > G, c.376A > G p.Lys126Glu, p.Lys126Glu, p.Lys126Glu No 4.3E−07 14:24306103:C:T c.371G > A, c.371G > A, c.371G > A p.Arg124Lys, p.Arg124Lys, p.Arg124Lys No 8.7E−07 14:24306105:CTCCCG:C c.364_368delCGGGA, p.Arg122fs, p.Arg122fs, p.Arg122fs Yes 4.3E−07 c.364_368delCGGGA, c.364_368delCGGGA 14:24306107:C:T c.367G > A, c.367G > A, c.367G > A p.Glu123Lys, p.Glu123Lys, p.Glu123Lys No 2.1E−05 14:24306112:C:A c.362G > T, c.362G > T, c.362G > T p.Gly121Val, p.Gly121Val, p.Gly121Val No 8.7E−07 14:24306115:A:G c.359T > C, c.359T > C, c.359T > C p.Leu120Pro, p.Leu120Pro, p.Leu120Pro No 4.3E−07 14:24306118:C:G c.356G > C, c.356G > C, c.356G > C p.Gly119Ala, p.Gly119Ala, p.Gly119Ala No 4.3E−07 14:24306121:T:C c.353A > G, c.353A > G, c.353A > G p.Tyr118Cys, p.Tyr118Cys, p.Tyr118Cys No 4.3E−07 14:24306122:A:G c.352T > C, c.352T > C, c.352T > C p.Tyr118His, p.Tyr118His, p.Tyr118His No 2.2E−06 14:24306126:CAG:C c.346_347delCT, p.Leu116fs, p.Leu116fs, p.Leu116fs Yes 4.3E−07 c.346_347delCT, c.346_347delCT 14:24306127:A:G c.347T > C, c.347T > C, c.347T > C p.Leu116Pro, p.Leu116Pro, p.Leu116Pro No 4.3E−07 14:24306139:T:G c.337 − 2A > C, Yes 4.3E−07 c.337 − 2A > C, c.337 − 2A > C 14:24306373:C:G c.336 + 1G > C, Yes 2.2E−06 c.336 + 1G > C, c.336 + 1G > C 14:24306374:C:G c.336G > C, c.336G > C, c.336G > C p.Arg112Ser, p.Arg112Ser, p.Arg112Ser No 4.3E−06 14:24306375:C:T c.335G > A, c.335G > A, c.335G > A p.Arg112Lys, p.Arg112Lys, p.Arg112Lys No 1.7E−06 14:24306382:G:T c.328C > A, c.328C > A, c.328C > A p.Pro110Thr, p.Pro110Thr, p.Pro110Thr No 1.7E−05 14:24306383:G:T c.327C > A, c.327C > A, c.327C > A p.Ser109Arg, p.Ser109Arg, p.Ser109Arg No 4.3E−07 14:24306384:C:G c.326G > C, c.326G > C, c.326G > C p.Ser109Thr, p.Ser109Thr, p.Ser109Thr No 4.3E−07 14:24306384:C:T c.326G > A, c.326G > A, c.326G > A p.Ser109Asn, p.Ser109Asn, p.Ser109Asn No 1.7E−06 14:24306386:C:G c.324G > C, c.324G > C, c.324G > C p.Trp108Cys, p.Trp108Cys, p.Trp108Cys No 1.3E−06 14:24306388:A:G c.322T > C, c.322T > C, c.322T > C p.Trp108Arg, p.Trp108Arg, p.Trp108Arg No 1.3E−06 14:24306391:T:C c.319A > G, c.319A > G, c.319A > G p.Ser107Gly, p.Ser107Gly, p.Ser107Gly No 4.3E−07 14:24306392:C:G c.318G > C, c.318G > C, c.318G > C p.Gln106His, p.Gln106His, p.Gln106His No 4.3E−07 14:24306397:C:T c.313G > A, c.313G > A, c.313G > A p.Gly105Ser, p.Gly105Ser, p.Gly105Ser No 8.7E−07 14:24306399:G:A c.311C > T, c.311C > T, c.311C > T p.Ser104Phe, p.Ser104Phe, p.Ser104Phe No 1.7E−06 14:24306402:T:A c.308A > T, c.308A > T, c.308A > T p.Gln103Leu, p.Gln103Leu, p.Gln103Leu No 2.6E−06 14:24306408:A:G c.302T > C, c.302T > C, c.302T > C p.Val101Ala, p.Val101Ala, p.Val101Ala No 3.9E−06 14:24306409:C:G c.301G > C, c.301G > C, c.301G > C p.Val101Leu, p.Val101Leu, p.Val101Leu No 4.3E−07 14:24306411:A:G c.299T > C, c.299T > C, c.299T > C p.Met100Thr, p.Met100Thr, p.Met100Thr No 1.7E−06 14:24306422:G:C c.288C > G, c.288C > G, c.288C > G p.Asp96Glu, p.Asp96Glu, p.Asp96Glu No 8.7E−07 14:24306423:T:C c.287A > G, c.287A > G, c.287A > G p.Asp96Gly, p.Asp96Gly, p.Asp96Gly No 4.3E−07 14:24306424:C:T c.286G > A, c.286G > A, c.286G > A p.Asp96Asn, p.Asp96Asn, p.Asp96Asn No 1.3E−06 14:24306426:T:G c.284A > C, c.284A > C, c.284A > C p.Asp95Ala, p.Asp95Ala, p.Asp95Ala No 4.3E−07 14:24306426:TCCTC:T c.280_283delGAGG, p.Glu94fs, p.Glu94fs, p.Glu94fs Yes 8.7E−07 c.280_283delGAGG, c.280_283delGAGG 14:24306426:T:C c.284A > G, c.284A > G, c.284A > G p.Asp95Gly, p.Asp95Gly, p.Asp95Gly No 1.7E−06 14:24306427:C:T c.283G > A, c.283G > A, c.283G > A p.Asp95Asn, p.Asp95Asn, p.Asp95Asn No 6.1E−06 14:24306429:T:G c.281A > C, c.281A > C, c.281A > C p.Glu94Ala, p.Glu94Ala, p.Glu94Ala No 4.3E−07 14:24306430:C:T c.280G > A, c.280G > A, c.280G > A p.Glu94Lys, p.Glu94Lys, p.Glu94Lys No 4.3E−07 14:24306430:C:A c.280G > T, c.280G > T, c.280G > T p.Glu94*, p.Glu94*, p.Glu94* Yes 4.3E−07 14:24306430:C:G c.280G > C, c.280G > C, c.280G > C p.Glu94Gln, p.Glu94Gln, p.Glu94Gln No 4.3E−07 14:24306435:A:G c.275T > C, c.275T > C, c.275T > C p.Leu92Pro, p.Leu92Pro, p.Leu92Pro No 4.3E−07 14:24306435:A:T c.275T > A, c.275T > A, c.275T > A p.Leu92Gln, p.Leu92Gln, p.Leu92Gln No 3.0E−06 14:24306436:G:T c.274C > A, c.274C > A, c.274C > A p.Leu92Met, p.Leu92Met, p.Leu92Met No 4.3E−07 14:24306438:T:A c.272A > T, c.272A > T, c.272A > T p.Gln91Leu, p.Gln91Leu, p.Gln91Leu No 8.7E−07 14:24306448:C:G c.262G > C, c.262G > C, c.262G > C p.Asp88His, p.Asp88His, p.Asp88His No 4.3E−07 14:24306449:C:G c.261G > C, c.261G > C, c.261G > C p.Glu87Asp, p.Glu87Asp, p.Glu87Asp No 1.3E−06 14:24306450:T:TC c.259dupG, c.259dupG, c.259dupG p.Glu87fs, p.Glu87fs, p.Glu87fs Yes 1.7E−05 14:24306453:C:T c.257G > A, c.257G > A, c.257G > A p.Ser86Asn, p.Ser86Asn, p.Ser86Asn No 4.3E−07 14:24306454:T:C c.256A > G, c.256A > G, c.256A > G p.Ser86Gly, p.Ser86Gly, p.Ser86Gly No 4.3E−07 14:24306455:G:C c.255C > G, c.255C > G, c.255C > G p.Asp85Glu, p.Asp85Glu, p.Asp85Glu No 4.3E−07 14:24306457:C:T c.253G > A, c.253G > A, c.253G > A p.Asp85Asn, p.Asp85Asn, p.Asp85Asn No 4.3E−07 14:24306459:A:G c.251T > C, c.251T > C, c.251T > C p.Val84Ala, p.Val84Ala, p.Val84Ala No 8.7E−07 14:24306460:C:T c.250G > A, c.250G > A, c.250G > A p.Val84Met, p.Val84Met, p.Val84Met No 1.3E−06 14:24306467:TC:T c.242delG, c.242delG, c.242delG p.Gly81fs, p.Gly81fs, p.Gly81fs Yes 4.3E−07 14:24306468:C:G c.242G > C, c.242G > C, c.242G > C p.Gly81Ala, p.Gly81Ala, p.Gly81Ala No 1.7E−06 14:24306469:C:G c.241G > C, c.241G > C, c.241G > C p.Gly81Arg, p.Gly81Arg, p.Gly81Arg No 4.3E−07 14:24306470:A:C c.240T > G, c.240T > G, c.240T > G p.Asp80Glu, p.Asp80Glu, p.Asp80Glu No 4.3E−07 14:24306472:C:T c.238G > A, c.238G > A, c.238G > A p.Asp80Asn, p.Asp80Asn, p.Asp80Asn No 8.7E−07 14:24306474:T:C c.236A > G, c.236A > G, c.236A > G p.Glu79Gly, p.Glu79Gly, p.Glu79Gly No 8.7E−07 14:24306475:C:T c.235G > A, c.235G > A, c.235G > A p.Glu79Lys, p.Glu79Lys, p.Glu79Lys No 2.2E−06 14:24306483:A:T c.227T > A, c.227T > A, c.227T > A p.Val76Glu, p.Val76Glu, p.Val76Glu No 1.7E−06 14:24306489:G:A c.221C > T, c.221C > T, c.221C > T p.Thr74Ile, p.Thr74Ile, p.Thr74Ile No 1.3E−06 14:24306489:G:T c.221C > A, c.221C > A, c.221C > A p.Thr74Asn, p.Thr74Asn, p.Thr74Asn No 2.6E−06 14:24306498:C:T c.212G > A, c.212G > A, c.212G > A p.Gly71Glu, p.Gly71Glu, p.Gly71Glu No 4.3E−07 14:24306507:A:G c.203T > C, c.203T > C, c.203T > C p.Leu68Pro, p.Leu68Pro, p.Leu68Pro No 2.6E−06 14:24306513:G:GC c.196_197insG, p.Thr66fs, p.Thr66fs, p.Thr66fs Yes 4.3E−07 c.196_197insG, c.196_197insG 14:24306513:GT:G c.196delA, c.196delA, c.196delA p.Thr66fs, p.Thr66fs, p.Thr66fs Yes 1.7E−05 14:24306514:T:A c.196A > T, c.196A > T, c.196A > T p.Thr66Ser, p.Thr66Ser, p.Thr66Ser No 1.3E−06 14:24306517:C:T c.193G > A, c.193G > A, c.193G > A p.Glu65Lys, p.Glu65Lys, p.Glu65Lys No 3.0E−06 14:24306519:A:T c.191T > A, c.191T > A, c.191T > A p.Leu64*, p.Leu64*, p.Leu64* Yes 4.3E−07 14:24306519:A:G c.191T > C, c.191T > C, c.191T > C p.Leu64Ser, p.Leu64Ser, p.Leu64Ser No 8.7E−07 14:24306522:G:T c.188C > A, c.188C > A, c.188C > A p.Ala63Glu, p.Ala63Glu, p.Ala63Glu No 3.0E−06 14:24306524:C:T c.187 − 1G > A, Yes 4.3E−07 c.187 − 1G > A, c.187 − 1G > A 14:24306525:T:C c.187 − 2A > G, Yes 8.7E−07 c.187 − 2A > G, c.187 − 2A > G 14:24307369:A:C c.186 + 2T > G, Yes 2.6E−06 c.186 + 2T > G, c.186 + 2T > G 14:24307370:C:T c.186 + 1G > A, Yes 4.3E−07 c.186 + 1G > A, c.186 + 1G > A 14:24307370:C:A c.186 + 1G > T, Yes 4.3E−07 c.186 + 1G > T, c.186 + 1G > T 14:24307372:T:C c.185A > G, c.185A > G, c.185A > G p.Lys62Arg, p.Lys62Arg, p.Lys62Arg No 1.7E−06 14:24307373:T:C c.184A > G, c.184A > G, c.184A > G p.Lys62Glu, p.Lys62Glu, p.Lys62Glu No 4.3E−07 14:24307375:GC:G c.181delG, c.181delG, c.181delG p.Ala61fs, p.Ala61fs, p.Ala61fs Yes 1.7E−06 14:24307376:C:T c.181G > A, c.181G > A, c.181G > A p.Ala61Thr, p.Ala61Thr, p.Ala61Thr No 5.6E−06 14:24307376:C:G c.181G > C, c.181G > C, c.181G > C p.Ala61Pro, p.Ala61Pro, p.Ala61Pro No 4.3E−07 14:24307379:G:C c.178C > G, c.178C > G, c.178C > G p.Leu60Val, p.Leu60Val, p.Leu60Val No 1.3E−06 14:24307381:A:C c.176T > G, c.176T > G, c.176T > G p.Leu59Arg, p.Leu59Arg, p.Leu59Arg No 4.3E−07 14:24307381:A:G c.176T > C, c.176T > C, c.176T > C p.Leu59Pro, p.Leu59Pro, p.Leu59Pro No 4.3E−07 14:24307384:T:C c.173A > G, c.173A > G, c.173A > G p.Glu58Gly, p.Glu58Gly, p.Glu58Gly No 3.2E−05 14:24307391:G:T c.166C > A, c.166C > A, c.166C > A p.Arg56Ser, p.Arg56Ser, p.Arg56Ser No 4.3E−07 14:24307397:C:G c.160G > C, c.160G > C, c.160G > C p.Ala54Pro, p.Ala54Pro, p.Ala54Pro No 4.3E−07 14:24307397:C:T c.160G > A, c.160G > A, c.160G > A p.Ala54Thr, p.Ala54Thr, p.Ala54Thr No 3.5E−06 14:24307400:C:T c.157G > A, c.157G > A, c.157G > A p.Ala53Thr, p.Ala53Thr, p.Ala53Thr No 4.3E−07 14:24307406:G:T c.151C > A, c.151C > A, c.151C > A p.Leu51Met, p.Leu51Met, p.Leu51Met No 8.7E−07 14:24307408:C:A c.149G > T, c.149G > T, c.149G > T p.Gly50Val, p.Gly50Val, p.Gly50Val No 1.3E−06 14:24307412:TC:T c.144delG, c.144delG, c.144delG p.Gly50fs, p.Gly50fs, p.Gly50fs Yes 8.7E−07 14:24307414:C:T c.143G > A, c.143G > A, c.143G > A p.Arg48Gln, p.Arg48Gln, p.Arg48Gln No 1.2E−05 14:24307415:G:C c.142C > G, c.142C > G, c.142C > G p.Arg48Gly, p.Arg48Gly, p.Arg48Gly No 4.3E−07 14:24307415:G:A c.142C > T, c.142C > T, c.142C > T p.Arg48Trp, p.Arg48Trp, p.Arg48Trp No 1.1E−05 14:24307417:A:T c.140T > A, c.140T > A, c.140T > A p.Ile47Asn, p.Ile47Asn, p.Ile47Asn No 4.3E−07 14:24307418:T:C c.139A > G, c.139A > G, c.139A > G p.Ile47Val, p.Ile47Val, p.Ile47Val No 4.3E−07 14:24307420:G:T c.137C > A, c.137C > A, c.137C > A p.Thr46Asn, p.Thr46Asn, p.Thr46Asn No 4.3E−07 14:24307420:G:A c.137C > T, c.137C > T, c.137C > T p.Thr46Ile, p.Thr46Ile, p.Thr46Ile No 8.7E−07 14:24307426:T:A c.131A > T, c.131A > T, c.131A > T p.Lys44Met, p.Lys44Met, p.Lys44Met No 4.3E−07 14:24307428:G:C c.129C > G, c.129C > G, c.129C > G p.His43Gln, p.His43Gln, p.His43Gln No 4.3E−07 14:24307432:T:A c.125A > T, c.125A > T, c.125A > T p.Asp42Val, p.Asp42Val, p.Asp42Val No 6.1E−06 14:24307435:C:T c.122G > A, c.122G > A, c.122G > A p.Cys41Tyr, p.Cys41Tyr, p.Cys41Tyr No 4.3E−06 14:24307436:A:C c.121T > G, c.121T > G, c.121T > G p.Cys41Gly, p.Cys41Gly, p.Cys41Gly No 1.3E−06 14:24307436:A:G c.121T > C, c.121T > C, c.121T > C p.Cys41Arg, p.Cys41Arg, p.Cys41Arg No 4.3E−07 14:24307437:GAC:G c.118_119delGT, p.Val40fs, p.Val40fs, p.Val40fs Yes 4.3E−07 c.118_119delGT, c.118_119delGT 14:24307439:C:T c.118G > A, c.118G > A, c.118G > A p.Val40Ile, p.Val40Ile, p.Val40Ile No 4.3E−07 14:24307441:C:G c.116G > C, c.116G > C, c.116G > C p.Arg39Pro, p.Arg39Pro, p.Arg39Pro No 3.0E−06 14:24307444:A:G c.113T > C, c.113T > C, c.113T > C p.Phe38Ser, p.Phe38Ser, p.Phe38Ser No 4.3E−07 14:24307444:A:C c.113T > G, c.113T > G, c.113T > G p.Phe38Cys, p.Phe38Cys, p.Phe38Cys No 4.3E−07 14:24307450:C:G c.107G > C, c.107G > C, c.107G > C p.Arg36Pro, p.Arg36Pro, p.Arg36Pro No 2.6E−06 14:24307450:C:CGCTG c.103_106dupCAGC, p.Arg36fs, p.Arg36fs, p.Arg36fs Yes 4.3E−07 c.103_106dupCAGC, c.103_106dupCAGC 14:24307450:C:A c.107G > T, c.107G > T, c.107G > T p.Arg36Leu, p.Arg36Leu, p.Arg36Leu No 4.3E−07 14:24307453:T:C c.104A > G, c.104A > G, c.104A > G p.Gln35Arg, p.Gln35Arg, p.Gln35Arg No 1.7E−06 14:24307454:G:A c.103C > T, c.103C > T, c.103C > T p.Gln35*, p.Gln35*, p.Gln35* Yes 4.8E−06 14:24307459:G:T c.98C > A, c.98C > A, c.98C > A p.Pro33Gln, p.Pro33Gln, p.Pro33Gln No 4.3E−07 14:24307465:G:C c.92C > G, c.92C > G, c.92C > G p.Ala31Gly, p.Ala31Gly, p.Ala31Gly No 4.3E−07 14:24307466:C:G c.91G > C, c.91G > C, c.91G > C p.Ala31Pro, p.Ala31Pro, p.Ala31Pro No 4.3E−07 14:24307468:G:A c.89C > T, c.89C > T, c.89C > T p.Ser30Leu, p.Ser30Leu, p.Ser30Leu No 4.3E−07 14:24307472:T:A c.85A > T, c.85A > T, c.85A > T p.Thr29Ser, p.Thr29Ser, p.Thr29Ser No 4.3E−07 14:24307473:C:A c.84G > T, c.84G > T, c.84G > T p.Trp28Cys, p.Trp28Cys, p.Trp28Cys No 4.3E−07 14:24307474:C:G c.83G > C, c.83G > C, c.83G > C p.Trp28Ser, p.Trp28Ser, p.Trp28Ser No 4.3E−07 14:24307474:C:A c.83G > T, c.83G > T, c.83G > T p.Trp28Leu, p.Trp28Leu, p.Trp28Leu No 2.2E−06 14:24307477:A:C c.80T > G, c.80T > G, c.80T > G p.Val27Gly, p.Val27Gly, p.Val27Gly No 4.3E−07 14:24307478:C:T c.79G > A, c.79G > A, c.79G > A p.Val27Ile, p.Val27Ile, p.Val27Ile No 3.0E−06 14:24307480:C:T c.77G > A, c.77G > A, c.77G > A p.Arg26Lys, p.Arg26Lys, p.Arg26Lys No 1.3E−06 14:24307486:C:G c.71G > C, c.71G > C, c.71G > C p.Gly24Ala, p.Gly24Ala, p.Gly24Ala No 4.3E−07 14:24307486:C:T c.71G > A, c.71G > A, c.71G > A p.Gly24Glu, p.Gly24Glu, p.Gly24Glu No 1.3E−05 14:24307489:A:G c.68T > C, c.68T > C, c.68T > C p.Phe23Ser, p.Phe23Ser, p.Phe23Ser No 1.3E−06 14:24307489:A:C c.68T > G, c.68T > G, c.68T > G p.Phe23Cys, p.Phe23Cys, p.Phe23Cys No 8.7E−07 14:24307490:A:G c.67T > C, c.67T > C, c.67T > C p.Phe23Leu, p.Phe23Leu, p.Phe23Leu No 1.7E−06 14:24307498:CTTATA:C c.54_58delTATAA, p.Asn18fs, p.Asn18fs, p.Asn18fs Yes 2.2E−06 c.54_58delTATAA, c.54_58delTATAA 14:24307501:A:G c.56T > C, c.56T > C, c.56T > C p.Ile19Thr, p.Ile19Thr, p.Ile19Thr No 3.0E−06 14:24307502:T:C c.55A > G, c.55A > G, c.55A > G p.Ile19Val, p.Ile19Val, p.Ile19Val No 1.3E−06 14:24307502:T:A c.55A > T, c.55A > T, c.55A > T p.Ile19Leu, p.Ile19Leu, p.Ile19Leu No 8.7E−07 14:24307502:T:G c.55A > C, c.55A > C, c.55A > C p.Ile19Leu, p.Ile19Leu, p.Ile19Leu No 8.7E−07 14:24307507:G:C c.50C > G, c.50C > G, c.50C > G p.Ser17Cys, p.Ser17Cys, p.Ser17Cys No 1.7E−06 14:24307508:A:C c.49T > G, c.49T > G, c.49T > G p.Ser17Ala, p.Ser17Ala, p.Ser17Ala No 4.3E−07 14:24307510:A:G c.47T > C, c.47T > C, c.47T > C p.Val16Ala, p.Val16Ala, p.Val16Ala No 1.3E−06 14:24307511:C:T c.46G > A, c.46G > A, c.46G > A p.Val16Ile, p.Val16Ile, p.Val16Ile No 1.3E−06 14:24307514:A:AC c.42dupG, c.42dupG, c.42dupG p.Ser15fs, p.Ser15fs, p.Ser15fs Yes 1.3E−06 14:24307515:C:G c.42G > C, c.42G > C, c.42G > C p.Arg14Ser, p.Arg14Ser, p.Arg14Ser No 8.7E−07 14:24307516:C:A c.42 − 1G > T, Yes 2.6E−06 c.42 − 1G > T, c.42 − 1G > T 14:24307516:C:T c.42 − 1G > A, Yes 8.7E−07 c.42 − 1G > A, c.42 − 1G > A 14:24307818:C:T c.41G > A, c.41G > A, c.41G > A p.Arg14Lys, p.Arg14Lys, p.Arg14Lys No 4.3E−07 14:24307818:CTGAG:C c.37_40delCTCA, p.Leu13fs, p.Leu13fs, p.Leu13fs Yes 4.3E−07 c.37_40delCTCA, c.37_40delCTCA 14:24307819:T:C c.40A > G, c.40A > G, c.40A > G p.Arg14Gly, p.Arg14Gly, p.Arg14Gly No 3.0E−06 14:24307822:G:A c.37C > T, c.37C > T, c.37C > T p.Leu13Phe, p.Leu13Phe, p.Leu13Phe No 1.3E−06 14:24307830:CTG:C c.27_28delCA, p.Ser10fs, p.Ser10fs, p.Ser10fs Yes 4.3E−06 c.27_28delCA, c.27_28delCA 14:24307830:C:T c.29G > A, c.29G > A, c.29G > A p.Ser10Asn, p.Ser10Asn, p.Ser10Asn No 1.3E−06 14:24307834:G:A c.25C > T, c.25C > T, c.25C > T p.Pro9Ser, p.Pro9Ser, p.Pro9Ser No 8.7E−07 14:24307835:G:T c.24C > A, c.24C > A, c.24C > A p.Asn8Lys, p.Asn8Lys, p.Asn8Lys No 8.7E−07 14:24307837:T:G c.22A > C, c.22A > C, c.22A > C p.Asn8His, p.Asn8His, p.Asn8His No 4.3E−06 14:24307840:G:C c.19C > G, c.19C > G, c.19C > G p.Leu7Val, p.Leu7Val, p.Leu7Val No 4.3E−07 14:24307842:G:A c.17C > T, c.17C > T, c.17C > T p.Ala6Val, p.Ala6Val, p.Ala6Val No 2.6E−06 14:24307843:C:T c.16G > A, c.16G > A, c.16G > A p.Ala6Thr, p.Ala6Thr, p.Ala6Thr No 4.3E−07 14:24307848:A:G c.11T > C, c.11T > C, c.11T > C p.Leu4Pro, p.Leu4Pro, p.Leu4Pro No 4.3E−07 14:24307849:G:C c.10C > G, c.10C > G, c.10C > G p.Leu4Val, p.Leu4Val, p.Leu4Val No 4.3E−07 14:24307849:G:A c.10C > T, c.10C > T, c.10C > T p.Leu4Phe, p.Leu4Phe, p.Leu4Phe No 4.3E−07 14:24307850:G:C c.9C > G, c.9C > G, c.9C > G p.Tyr3*, p.Tyr3*, p.Tyr3* Yes 4.3E−07 14:24307851:T:TA c.7dupT, c.7dupT, c.7dupT p.Tyr3fs, p.Tyr3fs, p.Tyr3fs Yes 4.3E−07 14:24307852:A:G c.7T > C, c.7T > C, c.7T > C p.Tyr3His, p.Tyr3His, p.Tyr3His No 3.5E−06 14:24307853:C:G c.6G > C, c.6G > C, c.6G > C p.Glu2Asp, p.Glu2Asp, p.Glu2Asp No 1.3E−06 14:24307853:C:A c.6G > T, c.6G > T, c.6G > T p.Glu2Asp, p.Glu2Asp, p.Glu2Asp No 8.7E−07 14:24307856:CATGG:C c.−2_2delCCAT, p.Met1fs, p.Met1fs, p.Met1fs Yes 4.3E−07 c.−2_2delCCAT, c.−2_2delCCAT 14:24307856:C:T c.3G > A, c.3G > A, c.3G > A p.Met1?, p.Met1?, p.Met1? Yes 4.8E−06 14:24307857:A:T c.2T > A, c.2T > A, c.2T > A p.Met1?, p.Met1?, p.Met1? Yes 4.3E−07 14:24307857:A:G c.2T > C, c.2T > C, c.2T > C p.Met1?, p.Met1?, p.Met1? Yes 8.7E−07 14:24307858:T:C c.1A > G, c.1A > G, c.1A > G p.Met1?, p.Met1?, p.Met1? Yes 1.3E−06 14:24307921:C:A c.−62 − 1G > T, Yes 1.3E−06 c.−62 − 1G > T 14:24307921:C:T c.−62 − 1G > A, Yes 1.3E−06 c.−62 − 1G > A 14:24307921:CT:C c.−62 − 2delA, Yes 4.3E−07 c.−62 − 2delA C:P:R:A indicates the genomic coordinates of the genetic variant including chromosome (C), physical genomic position in base pairs (P), reference allele (R) and alternative allele (A) relative to build 38 of the Human Genome sequence by the Human Genome Reference Consortium. Coding DNA and protein changes follow the Human Genome Variation Society nomenclature and refer to three CIDEB transcripts annotated in the in the Ensembl database (URL: https://useast.ensembl.org/index.html). Annotations on these three transcripts are reported in the Table 23 in the following order: ENST00000258807, ENST00000554411, ENST00000336557. AAF indicates the alternative allele frequency. pLOF indicates predicted loss of function variant.

Example 3: Interaction of CIDEB Rare Coding Variants with Body Mass Index

It was hypothesized that rare coding variants in CIDEB may protect from liver disease by preventing excessive build-up of liver fat into enlarged and inflammation-prone lipid droplets. If that were the case, the protective association of CIDEB rare pLOF and missense variants might be stronger in individuals with higher adiposity who are exposed to a higher risk of liver steatosis and injury. Thus, interactions for rare coding variants in CIDEB with body mass index (BMI), the principal epidemiological risk factor for liver steatosis, were estimated. The association of CIDEB rare coding variants with lower ALT was amplified in individuals with higher BMI when BMI was modelled as a continuous variable (p_(interaction)=4.5×10⁻⁷ rare pLOF plus missense variants in CIDEB and P_(interaction)=0.0046 for pLOF variants in CIDEB, as shown in FIG. 4 ).

An interaction on ALT between rare coding variants in CIDEB and clinical categories of BMI was identified. Specifically, CIDEB rare coding variants were not associated with ALT levels in non-overweight individuals (per-allele beta in U/L, 0.1; 95% CI, −0.7 to 0.8; p=0.85), but were associated with −2.8 U/L lower ALT in obese individuals (95% CI, −3.6 to −2.1; p=1.7×10⁻¹³; p_(interaction) with BMI category=2.9×10⁻⁸; FIG. 5 , panel a and Table 24). This interaction was also observed for CIDEB pLOF variants (FIG. 5 , panel b and Table 24). Therefore, the protective association against liver damage observed in carriers of rare pLOF variants in CIDEB is greater in individuals with higher body mass index or who are categorically classified as overweight or obese.

TABLE 24 Interaction between rare pLOF or missense variants in CIDEB and BMI on ALT levels (genetic exposure for first three data lines = burden of pLOF or missense variants in CIDEB with AAF <1%; genetic exposure for last three data lines = burden of pLOF variants in CIDEB with AAF <1%) Interaction beta (95% CI) p-value for in SD units of linear ALT per each interaction Per allele beta additional between (95% CI) in SD Genotype counts, CIDEB allele CIDEB BMI units of ALT RR|RA|AA and kg/m² genotype category levels p-value genotypes unit of BMI and BMI Not −0.01 8.5 × 10⁻¹ 162,679|1,035|0 −0.08 4.5 × 10⁻⁷ Overweight (−0.05, 0.06) (−0.11, −0.05) (<25 kg/m2) Overweight −0.08 7.9 × 10⁻⁴ 213,922|1,423|2 (25 to <30 (−0.13, −0.03) kg/m2) Obese −0.21  1.7 × 10⁻¹³ 159,033|1,113|1 (≥30 kg/m2) (−0.26, −0.15) Not Overweight 0.03 5.7 × 10⁻¹ 163,479|235|0 −0.10 4.6 × 10⁻³ (<25 kg/m2) (−0.08, 0.15) (−0.16, −0.03) Overweight −0.10 5.8 × 10⁻² 215,051|296|0 (25 to <30 (−0.21, 0.00) kg/m2) Obese −0.25 8.5 × 10⁻⁵ 159,928|219|0 (≥30 kg/m2) (−0.37, −0.12) BMI indicates body mass index. BMI categories were defined according to the World Health Organization as follows: “non-overweight” (BMI<25 kg/m²), “overweight” (BMI≥25 and <30 kg/m²), “obesity” (BMI≥30). RR indicates the number of individuals carrying no rare missense or pLOF variants in CIDEB (homozygous non-carriers); RA indicates the number of individuals carrying rare missense or pLOF variants in a single CIDEB allele (heterozygous carriers); AA indicates the number of individuals carrying rare missense or pLOF variants in both CIDEB alleles (homozygous carriers); SD indicates standard deviation units; AAF indicates the alternative allele frequency; pLOF indicates predicted loss of function; CI indicates confidence interval; kg/m² kilograms per square meter.

Table 24 shows the association with ALT levels of rare pLOF or missense variants in CIDEB within BMI categories in a meta-analysis of the GHS and UKB cohorts and the estimates from the linear interaction analysis.

Given the significant interactions for CIDEB with BMI (this example) and PNPLA3 (Example 4) on ALT and potential for CIDEB to affect liver fat through experimental evidence (Example 5), it was hypothesized that rare coding variants in CIDEB are associated with liver fat and that the association is more pronounced in overweight individuals. Rare coding variants in CIDEB were significantly associated with MRI-measured liver fat (Table 25): rare pLOF variants were associated with lower liver fat in overweight or obese individuals (per-allele beta in % units of liver fat fraction, −1.5%; 95% CI, −3.0% to −0.1%; p=0.04). In addition, a significant interaction was found between rare pLOF or missense variants in CIDEB and BMI on MRI-measured liver fat (p-interaction=0.02).

TABLE 25 Association results for the interaction between carriers of rare coding variant in CIDEB and overweight or obese individuals on MRI measured liver fat Beta (95% CI) Clinical units, in SD units % liver fat Allele Exposure per allele fraction P count CIDEB (pLOF; AAF <1%) in 0.10 0.51 0.61 14,892|19|0 not-overweight individuals (−0.30, 0.51) (−1.46, 2.49) CIDEB (pLOF; AAF <1%) −0.31 −1.54 0.04 22,261|35|0 in Overweight or Obese (−0.61, −0.02) (−2.99, −0.08) individuals Interaction estimate of −0.42 −2.05 0.10 CIDEB (pLOF; AAF <1%) * (−0.92, 0.08) (−4.49, 0.40) Overweight or obese CIDEB (pLOF + missense 0.18 0.88 0.07 14,947|79|0 variants; AAF <1%) in not- (−0.02, 0.37) (−0.08, 1.84) overweight individuals CIDEB (pLOF + missense −0.12 −0.60 0.10 22,357|143|0 variants; AAF <1%) in (−0.27, 0.02) (−1.31, 0.12) Overweight or Obese individuals Interaction estimate of −0.30 −1.45 0.02 CIDEB (pLOF + missense (−0.54, −0.05) (−2.67, −0.23) variants; AAF <1%) * Overweight or obese

A linear regression was performed between PDFF and CIDEB rare coding variants within not-overweight and overweight or obese individuals separately. Interaction estimates were calculated in the full model, in each ancestry separately and meta-analyzed—same as the discovery analysis. Abbreviations: pLOF, predicted loss of function; SD, standard deviation; P, p-value; AAF, alternate allele frequency.

The proportion of liver disease by CIDEB genotypes and BMI categories were also estimated and it was found that the difference in proportion of liver disease in CIDEB rare coding variant carriers versus non-carriers was highest in the obesity category (FIG. 6 ).

Example 4: Rare Coding Variants in CIDEB Interact with PNPLA3 Genotypes and Show Additive Associations with HSD17B13 Genotypes

A common missense variant in the Patatin Like Phospholipase Domain Containing 3 (PNPLA3) gene, encoding a p.Ile148Met (dbSNP rsID, r5738409; C>G substitution) missense change in the PNPLA3 protein is one of the most common and strongest genetic risk factors for liver damage (measured by ALT levels), alcoholic and non-alcoholic liver disease and cirrhosis (Nat. Genet., 2008, 40, 1461-5; and Nat. Genet., 2010, 42, 21-3). In the exome-sequencing dataset, the 148Met risk allele was strongly associated with higher ALT levels (per allele beta in SD units of ALT, 0.11; 95% confidence interval, 0.10, 0.11; p<1.0×10⁻³⁰⁰) consistent with previous literature.

A statistically significant interaction was observed between rare coding variants in CIDEB and the common PNPLA3 148Met risk allele on ALT (Table 26 and FIG. 7 ).

TABLE 26 Interaction between rare pLOF or missense variants in CIDEB and PNPLA3 Ile148Met on ALT levels Interaction p-value for beta (95% CI) linear in SD units of interaction PNPLA3 rs738409 Per allele ALT per each between (Ile148Met) beta Genotype additional CIDEB genotype group, (95% CI) in counts, CIDEB allele genotype CIDEB genotype SD units of RR|RA|AA and PNPLA3 and PNPLA3 exposure ALT levels p-value genotypes 148Met allele genotype C/C (p.148 Ile/Ile), −0.06 1.8E−03 329883|2190|0 −0.07 0.010 CIDEB pLOF plus (−0.10, −0.02) (−0.12, −0.02) any missense C/G (p.148 −0.14 4.7E−07 182915|1241|1 Ile/Met), CIDEB (−0.19, −0.09) pLOF plus any missense G/G (p.148 −0.18 1.8E−02 26420|178|2 Met/Met), CIDEB (−0.34, −0.03) pLOF plus any missense C/C (p.148 −0.04 3.3E−01 331406|471|0 −0.14 0.019 Ile/Ile), (−0.13, 0.04) (−0.26, −0.02) CIDEB pLOF C/G (p.148 −0.24 1.1E−04 183902|255|0 Ile/Met), (−0.36, −0.12) CIDEB pLOF G/G (p.148 −0.20 2.8E−01 26141|34|0 Met/Met), (−0.55, 0.16) CIDEB pLOF RR indicates the number of individuals carrying no rare missense or pLOF variants in CIDEB (homozygous non-carriers); RA indicates the number of individuals carrying rare missense or pLOF variants in a single CIDEB allele (heterozygous carriers); AA indicates the number of individuals carrying rare missense or pLOF variants in both CIDEB alleles (homozygous carriers); SD indicates standard deviation units; AAF indicates the alternative allele frequency; pLOF indicates predicted loss of function; CI indicates confidence interval.

The first section of Table 26 describes the burden of pLOF or missense variants in CIDEB with AAF<1% as the genetic exposure; second section describes the burden of only pLOF variants in CIDEB with AAF<1% as the genetic exposure. Table 26 shows the association with ALT levels of CIDEB genotype within PNPLA3 rs738409 Ile148Met genotype categories in a meta-analysis of the GHS and UKB cohorts and the estimates from the linear interaction analysis.

The association with lower ALT levels for rare pLOF variants in CIDEB was strongest in homozygous carriers of the 148Met risk allele (G/G group), with an estimated effect size that was 5 times larger in a protective direction than what was observed in homozygous carriers of the PNPLA3 148 Ile allele (C/C group; Table 26). Therefore, the protective association against liver damage observed in carriers of rare pLOF or missense variants in CIDEB is greater in individuals carrying the common PNPLA3 148Met risk allele.

No significant interactions were found between rare coding variants in CIDEB and the splice variant rs72613567 which causes loss of function in HSDB17B13 and has been shown to protect against liver disease (N. Engl. J. Med., 2018, 378, 1096-106) (Table 27). These results indicate that rare coding variants in CIDEB have additive protective associations to those of rs72613567-TA in HSD17B13.

TABLE 27 Interaction between rare pLOF or missense variants in CIDEB (AAF <1%) and rs72613567 (HSD17B13 splice variant) on ALT levels p-value Per allele for linear rs72613567-TA beta Genotype interaction (splice (95% CI) in counts, between CIDEB LOF variant SD units of RR|RA|AA genotype and in HSD17B13) ALT levels p-value genotypes rs72613567 T/T −1.2 2E−04 271776|1629|1 0.88 (−1.9, −0.6) T/TA −1.7 3E−06 204162|1231|0 (−2.5, −1.0) TA/TA −0.4 6.4E−01  38700|208|0 (−2.2, 1.3)

Example 5: CIDEB is Expressed in Hepatocytes at the Surface of Lipid Droplets, Predicted-Loss-of-Function Variants in CIDEB are Associated with Lower Gene Expression in Liver, and Inhibition of CIDEB Expression Via siRNA Decreases Lipid Droplet Size and Reduces Lipid Accumulation in HepG2 Cells

The mRNA expression of CIDEB was examined across tissues in humans from the Genotype Tissue Expression consortium (GTEx) and it was found that CIDEB is most highly expressed in liver among the GTEx tissues (FIG. 8 ). The mRNA expression of CIDEB was also examined among cell types in data from the Human Protein Atlas (HPA) and found that CIDEB is most highly expressed in hepatocytes (FIG. 8 ).

Given that CIDEB is expressed in liver, the impact of predicted loss-of-function (pLOF) variants in the gene was investigated using liver RNASeq data from bariatric surgery patients from GHS. Using liver RNASeq, the impact of two pLOF variants (c.336+1G>A, and Lys153*) was evaluated. These were the only two pLOF variants present in the 2,304 bariatric surgery patients in GHS who underwent RNASeq. Two heterozygous carriers for each of the two variant sites were found and expression levels for CIDEB below the 25th percentile in each of the four carriers were observed (FIG. 9 ). Both carriers of the Lys153* variant expressed reads containing the stop-gained mutation much less frequently than those carrying the reference allele (expected proportion under the assumption of no impact, 50%; Carrier 1 proportion, 9.9%; p_(binomial) for the observed imbalance=1.8×10⁻⁸⁹; Carrier 2 proportion, 11.9%; p_(binomial)=5.2×10⁻⁵¹; FIG. 9 ), indicating that the variant is subject to nonsense mediated decay and results in loss of a copy of CIDEB. In carriers of the c.336+1G>A variant, none of the RNASeq reads with spliced sequences that overlap the variant position carried the splice-donor allele. However, RNAseq reads whose unspliced sequences overlapped the position of the splice site were enriched for the splice-donor variant compared to the reference allele (expected proportion under the assumption of no impact, 50%; Carrier 3 proportion, 78.0%; p_(binomial)=4.1×10⁻⁰⁶; Carrier 4 proportion, 76.5%; p_(binomial)=2.0×10⁻⁰⁴; FIG. 9 ), indicating that the variant results in intron retention.

Given that the protective loss-of-function variants in CIDEB were associated with lower liver expression of this gene, the effects of siRNA-mediated knockdown of CIDEB were studied in human hepatocellular carcinoma HepG2 cells with and without treatment with oleic acid, a monosaturated omega-9 fatty acid that is routinely used to mimic steatosis conditions in vitro. In particular, HepG2 human hepatoma cells were treated with control siRNA or siRNA targeting CIDEB. 24 hours after siRNA transfection, cells were treated with 0 μM or 400 μM oleic acid for 24 hours. Endogenous CIDEB protein localized to punctae on the surfaces of lipid droplets and at the interfaces of adjacent lipid droplets in both conditions in cells treated with a non-targeting pool of control siRNA (FIG. 10 , Panel A); no CIDEB staining was observed in cells treated with CIDEB siRNA to inhibit CIDEB expression (FIG. 10 , Panel B), demonstrating the specificity of the CIDEB antibody used. For each treatment, the left-side image shows the merge of all three stains and the right-side image shows staining of CIDEB only. Further quantification showed that the CIDEB siRNA inhibited CIDEB mRNA expression by 71% and inhibited CIDEB protein expression by 89% (FIG. 10 , Panel C). GAPDH was used as loading and normalization control.

Silencing of CIDEB did not affect lipid droplet number or average lipid droplet size, cell triglyceride content or cell lipid droplet staining in the basal condition (FIG. 10 , Panels D, E, F, G, and H). CIDEB siRNA-treated cells secreted less IL-8 (FIG. 10 , Panel I), a proinflammatory cytokine linked to NAFLD progression, consistent with the genetic associations showing decreased risk of inflammatory liver diseases such as NASH and cirrhosis. Cells were next treated with oleic acid to induce fat accumulation. Oleic acid resulted in the appearance of larger lipid droplets in cells treated with control siRNA in a manner proportional to the amount of oleic acid administered (FIG. 10 , Panel J), with increased average lipid droplet size, cell triglyceride content and cell lipid droplet staining (FIG. 10 , Panels E, F, G, and H). Numerical, non statistically-significant reductions in average cell triglyceride content or cell lipid droplet staining were observed in CIDEB siRNA-treated cells (FIG. 10 , Panels G and H), in line with the genetic association results for liver fat fraction. However, inhibition of CIDEB expression prior to oleic acid treatment resulted in an increased number of smaller lipid droplets compared to cells treated with control siRNA, with significantly reduced average lipid droplet size (p<0.0001) and increased number of lipid droplets per cell (p<0.01) (FIG. 10 , Panels D, E, and F).

Various modifications of the described subject matter, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference (including, but not limited to, journal articles, U.S. and non-U.S. patents, patent application publications, international patent application publications, gene bank accession numbers, and the like) cited in the present application is incorporated herein by reference in its entirety. 

What is claimed is:
 1. A method of treating a subject with a cell death inducing DFFA like effector B (CIDEB) inhibitor, wherein the subject has a liver disease or is at risk of developing a liver disease, the method comprising the steps of: determining whether the subject has a CIDEB variant nucleic acid molecule by: obtaining or having obtained a biological sample from the subject; and performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising the CIDEB variant nucleic acid molecule, wherein the CIDEB variant nucleic acid molecule is a missense variant, a splice-site variant, a stop-gain variant, a start-loss variant, a stop-loss variant, a frameshift variant, or an in-frame indel variant, or a variant that encodes a truncated CIDEB polypeptide; and administering or continuing to administer the CIDEB inhibitor in a standard dosage amount to a CIDEB reference subject; and administering or continuing to administer the CIDEB inhibitor in a dosage amount that is the same as or less than a standard dosage amount to a subject that is heterozygous for the CIDEB variant nucleic acid molecule; wherein the presence of a genotype having the CIDEB variant nucleic acid molecule indicates the subject has a decreased risk of developing the liver disease or has a decreased risk of developing a more severe form of the liver disease.
 2. The method of claim 1, wherein the subject is CIDEB reference, and the subject is administered or continued to be administered the CIDEB inhibitor in a standard dosage amount.
 3. The method of claim 1, wherein the subject is heterozygous for the CIDEB variant nucleic acid molecule, and the subject is administered or continued to be administered the CIDEB inhibitor in a dosage amount that is the same as or less than a standard dosage amount.
 4. The method of claim 1, wherein the CIDEB variant nucleic acid molecule is a genomic nucleic acid molecule.
 5. The method of claim 1, wherein the CIDEB variant nucleic acid molecule is an mRNA molecule.
 6. The method of claim 1, wherein the CIDEB variant nucleic acid molecule is a cDNA molecule produced from an mRNA molecule.
 7. The method of claim 1, wherein the CIDEB variant nucleic acid molecule comprises 14:24305635:A:AGTAG, 14:24305641:A:C, 14:24305650:G:A, 14:24305657:C:A, 14:24305662:G:T, 14:24305667:T:C, 14:24305671:C:A, 14:24305671:C:G, 14:24305701:A:T, 14:24305709:C:T, 14:24305718:A:G, 14:24305721:T:C, 14:24305728:G:GGCCTT, 14:24305743:T:C, 14:24305948:T:C, 14:24305966:C:T, 14:24305974:T:C, 14:24305980:TCA:T, 14:24305988:C:T, 14:24306014:C:T, 14:24306034:A:C, 14:24306041:C:G, 14:24306044:G:A, 14:24306047:G:A, 14:24306051:T:G, 14:24306064:T:C, 14:24306074:A:G, 14:24306077:G:C, 14:24306082:A:G, 14:24306083:T:A, 14:24306095:G:A, 14:24306122:A:G, 14:24306134:C:G, 14:24306373:C:G, 14:24306379:T:C, 14:24306382:G:A, 14:24306383:G:T, 14:24306426:T:G, 14:24306437:C:G, 14:24306439:G:C, 14:24306442:A:G, 14:24306444:A:G, 14:24306457:C:T, 14:24306463:C:T, 14:24306469:C:T, 14:24306480:A:G, 14:24306486:A:C, 14:24306504:A:G, 14:24306519:A:G, 14:24307382:G:C, 14:24307405:A:G, 14:24307417:A:T, 14:24307421:T:A, 14:24307441:C:A, 14:24307444:A:C, 14:24307444:A:G, 14:24307450:C:CGCTG, 14:24307461:TG:T, 14:24307469:AG:A, 14:24307474:C:T, 14:24307475:A:G, 14:24307833:G:C, 14:24307851:T:TAC, 14:24306426:T:C, 14:24307849:G:C, 14:24307448:G:T, 14:24305671:C:T, 14:24305663:C:T, 14:24305686:C:G, 14:24307829:A:C, 14:24307818:CTGAG:C, 14:24307856:C:T, 14:24306423:T:C, 14:24306061:AC:A, 14:24307390:C:T, 14:24306382:G:T, 14:24306373:C:T, 14:24305733:T:C, 14:24307858:T:C, 14:24306387:C:T, 14:24305637:T:C, 14:24306062:C:T, 14:24307853:C:G, 14:24307450:C:G, 14:24306052:TG:T, 14:24305673:G:A, 14:24306043:C:T, 14:24307834:G:A, 14:24306417:C:T, 14:24307451:G:A, 14:24307436:A:C, 14:24305953:ACTTT:A, 14:24306489:G:T, 14:24307441:C:T, 14:24306375:C:T, 14:24305657:C:G, 14:24306427:C:T, 14:24306524:C:T, 14:24307516:C:A, 14:24307840:G:C, 14:24307501:A:G, 14:24305968:A:C, 14:24305986:C:T, 14:24307441:C:G, 14:24307459:G:T, 14:24306017:T:A, 14:24307424:G:A, 14:24306072:G:T, 14:24307423:C:T, 14:24307450:C:T, 14:24306420:G:A, 14:24307454:G:A, 14:24305653:C:T, 14:24307442:G:A, 14:24306002:C:T, 14:24306076:C:T, 14:24305664:C:T, 14:24305961:TG:T, 14:24305706:A:G, 14:24305946:C:T, 14:24306455:G:C, 14:24307468:G:A, 14:24307825:A:C, 14:24306110:G:A, 14:24305710:C:T, 14:24307483:C:T, 14:24306459:A:G, 14:24305754:C:T, 14:24305650:G:C, 14:24305691:C:T, 14:24306508:G:C, 14:24306039:G:T, 14:24306139:T:C, 14:24306391:T:C, 14:24306373:C:A, 14:24307498:C:T, 14:24307415:G:A, 14:24306138:CTG:C, 14:24307453:T:C, 14:24305692:G:A, 14:24305683:C:G, 14:24307484:G:A, 14:24307385:C:T, 14:24306519:A:T, 14:24307839:A:C, 14:24305965:C:T, 14:24305988:CAT:C, 14:24306087:C:G, 14:24307439:C:T, 14:24307477:A:C, 14:24306436:G:T, 14:24306507:A:G, 14:24307397:C:T, 14:24307495:G:A, 14:24306034:A:T, 14:24306013:G:A, 14:24307381:A:G, 14:24306383:G:C, 14:24305638:A:G, 14:24307420:G:A, 14:24306020:C:T, 14:24306470:A:C, 14:24307435:C:T, 14:24306469:C:G, 14:24306451:C:T, 14:24306403:G:A, 14:24307515:C:G, 14:24307489:A:G, 14:24307414:C:T, 14:24306483:A:G, 14:24305755:G:A, 14:24305766:C:T, 14:24306064:T:G, 14:24307516:C:G, 14:24305766:C:G, 14:24306489:G:A, 14:24306097:T:C, 14:24305763:T:G, 14:24307447:G:A, 14:24307402:G:A, 14:24305972:C:G, 14:24306423:T:G, 14:24305974:T:TG, 14:24307411:T:C, 14:24306121:T:C, 14:24307516:C:T, 14:24306424:C:T, 14:24306039:G:C, 14:24307853:C:A, 14:24306388:A:G, 14:24305990:T:C, 14:24307822:G:GT, 14:24305640:G:A, 14:24307418:T:C, 14:24305758:G:C, 14:24306131:C:T, 14:24305953:A:G, 14:24305730:C:A, 14:24306418:A:G, 14:24306059:AC:A, 14:24307842:G:A, 14:24307837:T:G, 14:24306095:G:T, 14:24306109:C:T, 14:24307822:G:A, 14:24306077:G:A, 14:24307824:A:T, 14:24306080:C:T, 14:24305649:C:T, 14:24306433:G:GA, 14:24306420:G:C, 14:24305658:T:G, 14:24306472:C:T, 14:24307412:TC:T, 14:24306062:C:A, 14:24306044:G:C, 14:24306047:G:T, 14:24306126:CAG:C, 14:24306449:C:G, 14:24307391:G:A, or 14:24307857:A:C, according to GRCh38/hg38 human genome assembly coordinates.
 8. The method of claim 1, wherein the sequence analysis comprises sequencing at least a portion of the nucleotide sequence of the CIDEB genomic nucleic acid molecule, CIDEB mRNA molecule, or CIDEB cDNA molecule produced from an mRNA molecule in the biological sample.
 9. The method of claim 8, wherein the sequence analysis comprises: a) contacting the biological sample with a primer hybridizing to a portion of the nucleotide sequence of the CIDEB nucleic acid molecule that is proximate to a CIDEB variant nucleic acid molecule position; b) extending the primer at least through the CIDEB variant nucleic acid molecule position; and c) determining whether the extension product of the primer comprises a variant nucleotide at the CIDEB variant nucleic acid molecule position.
 10. The method of claim 8, wherein the sequence analysis comprises sequencing the entire nucleic acid molecule in the biological sample.
 11. The method of claim 1, wherein the sequence analysis comprises: a) amplifying at least a portion of the CIDEB nucleic acid molecule in the biological sample, wherein the portion comprises a CIDEB variant nucleic acid molecule position; b) labeling the amplified nucleic acid molecule with a detectable label; c) contacting the labeled nucleic acid molecule with a support comprising an alteration-specific probe, wherein the alteration-specific probe comprises a nucleotide sequence which hybridizes under stringent conditions to the CIDEB variant nucleic acid molecule position; and d) detecting the detectable label.
 12. The method of claim 1, wherein the sequence analysis comprises: contacting the CIDEB nucleic acid molecule in the biological sample with an alteration-specific probe comprising a detectable label, wherein the alteration-specific probe comprises a nucleotide sequence which hybridizes under stringent conditions to a CIDEB variant nucleic acid molecule position; and detecting the detectable label.
 13. The method of claim 1, further comprising determining the subject's gene burden of having a CIDEB variant nucleic acid molecule.
 14. The method of claim 1, further comprising administering a patatin-like phospholipase domain containing 3 (PNPLA3) inhibitor.
 15. The method of claim 1, further comprising administering a hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) inhibitor.
 16. The method of claim 14, further comprising detecting the presence or absence of a PNPLA3 variant nucleic acid molecule encoding PNPLA3 Ile148Met or Ile144Met polypeptide in a biological sample from the subject.
 17. The method of claim 14, wherein the subject has a PNPLA3 variant nucleic acid molecule encoding PNPLA3 Ile148Met or Ile144Met polypeptide, and the subject is administered a PNPLA3 inhibitor.
 18. The method of claim 14, wherein the PNPLA3 inhibitor is AZD2693.
 19. The method of claim 15, further comprising detecting the presence or absence of a nucleic acid molecule encoding a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide and/or a reference HSD17B13 polypeptide or a functional HSD17B13 polypeptide in a biological sample from the subject.
 20. The method of claim 15, wherein the HSD17B13 inhibitor is ARO-HSD or ALN-HSD.
 21. The method of claim 1, further comprising administering a therapeutic agent for treating a liver disease to the subject.
 22. The method of claim 21, wherein the therapeutic agent for treating a liver disease comprises semaglutide.
 23. The method of claim 1, wherein the liver disease is fatty liver disease.
 24. The method of claim 1, wherein the liver disease is non-alcoholic fatty liver disease (NAFLD).
 25. The method of claim 1, wherein the liver disease is non-alcoholic steatohepatitis (NASH).
 26. The method of claim 1, wherein the liver disease is liver cirrhosis.
 27. The method of claim 1, wherein the liver disease is liver fibrosis. 